Benzoxathiepine derivatives and their use as medicines

ABSTRACT

The invention concerns 3-arylthio-propyl-amino-3,4-dihydro-2H-1,5-aryloxathiepin derivatives of general formula (I), wherein: R1 and R2, identical or different, represent a hydrogen atom, a fluorine atom or a chlorine atom, a hydroxy group, an alkyl, cyclopropyl, alkoxy, cyclopropoxy radical or when they occupy adjacent positions, form with the carbon atoms bearing them a carbon-containing cycle or an oxygen-containing heterocycle with five non-aromatic rings; R3 represents an alkyl radical, a hydroxy group or a methoxy radical; R4 represents a hydrogen atom or a methyl radical; and R5 and R6, identical or different represent a hydrogen atom, an alkyl, alkoxy, alkylthio, alkylamino radical, or the groups OR4 and R5 form with the carbons which bear them a non-aromatic heterocycle with five or six rings containing at least an oxygen atom; and their pharmaceutically acceptable additions salts

This application is 371 of PCT/FR02/00969 filed on Mar. 20, 2002, whichclaims benefit of the foreign application, FRANCE 01/03877 filed on Mar.22, 2001.

A subject matter of the present invention is3-arylthiopropylamino-3,4-dihydro-2H-1,5-benzoxathiepine derivatives,their process of preparation and their use as medicaments.

Indole derivatives of formula:

in which:

-   R₁=C₃–C₁₂ cycloalkyl or poly(C₃–C₁₂)cycloalkyl;-   A=(CH₂)_(n)CO, SO₂, S(O), NHCO, (CH₂)_(n)COO, SCO, O(CH₂)_(n)CO or    HC═CHCO;-   R′₂=C₁–C₆ alkyl, HC═CH₂, CCH, (CH₂)_(n′)CH═CH₂, (CH₂)_(n′)CCH,    (CH₂)_(n)Ar, (CH₂)_(n)OR′, (CH₂)_(n)OAr, (CH₂)_(n)CO₂R′ or    (CH₂)_(n)NR₅R₆;-   R₉=H, C₁–C₆ alkyl, (CH₂)_(n)CO₂R′, (CH₂)_(n)OAr, (CH₂)_(n)Ar or    (CH₂)_(n)NR₅R₆;-   R′₁₂=R′₁₃=R′₁₄=halogen;-   X and Y=O, S, N, CH₂, CHR₁₂, NR₁₂, NR₁₂CO, CN, C═C, CO or a bond;-   w=0 or 1; n=n′=0–6;-   R₅ and R₆=H or C₁–C₆ alkyl;-   R′=H or C₁–C₆ alkyl;-   Ar=carbon- or heteroaromatic, carbo- or heterocyclic, mono- or    polycyclic residue;-   R₁₂=H;    are claimed in international application WO 93/03721 as    colecystokinin antagonists of use in the treatment of depression.

3-Oxo-3,4-dihydro-2H-1,5-benzoxathiepines of formula:

in which:

-   R₁ and R₂=H, alkyl, alkoxy, OH or halo;-   R₃ and R₄=H, alkyl, cycloalkyl, aralkyl or heterocyclic;-   X=H, CO₂H, alkyl or aryl;-   Y=(C═O) or CH₂OR₅;-   m=0–2; n=1–6;-   R₅=H, C₁–C₆ alkyl, phenyl(C₁–C₆)alkyl which is unsubstituted or    substituted by 1 to 3 halogen atoms or a C₁–C₄ alkyl or C₁–C₄ alkoxy    or methylenedioxy or amino or nitro or hydroxyl group; a    unsubstituted carbamoyl group or a carbamoyl group substituted by a    group which is C₁–C₄ alkyl, unsubstituted phenyl or phenyl    substituted by 1 to 3 halogen atoms or C₁–C₄ alkyl or C₁–C₄ alkoxy    or methylenedioxy or amino or nitro or hydroxyl; a unsubstituted    phenyl(C₁–C₄)alkyl group or a phenyl(C₁–C₄)alkyl group substituted    by 1 to 3 halogen atoms or C₁–C₄ alkyl or C₁–C₄ alkoxy or    methylenedioxy or amino or nitro or hydroxyl,    are claimed in patents EP 300 088 and EP 145 494 and in    international application WO 85/02617 both as serotonin 5-HT₂    receptor subtype antagonists and calcium channel antagonists. The    same compounds are claimed in patent EP 667 156 as agents of use in    the treatment of ocular diseases.

The preparation of3-amino-3,4-dihydro-2H-1,5-benzoxathiepine-4-carbonitriles of formula:

in which:

-   R=H, OCH₃, CH₃ or Cl;    is disclosed in Chem. Pharm. Bull., 1987, 35, 1919 and WO 85/02617.

1,5-Benzoxathiepine-2-one-4-aryls are reported as benzodiazepine analogsin Synth. Commun., 1996, 26, 4459 and Med. Sci. Res., 1996, 24, 589.

4-Hydroxy-1,5-benzoxathiepines are described in Phosphorus Sulfur, 1983,14, 151 and J. Heterocyclic. Chem., 1994, 31, 1151.

1,5-Benzoxathiepine-2,4-diones are reported in J. Heterocyclic. Chem.,1982, 19, 1241 and Rapid Commun. Mass Spectrom., 1991, 5, 137.

Variously substituted 2,3-dihydro-1,4-benzothiazepines, related todiltiazem, are described in J. Org. Chem., 1999, 64, 2219. Others areclaimed as bradykinin receptor agonists (FR 2 756 566; J. Med. Chem.,2000, 43, 2382 and 2387) or as neuropeptide Y inhibitors (WO 98/35941)or as conversion enzyme inhibitors (U.S. Pat. No. 5,723,457).

Diphosphonic acids of formula:

in which:

-   R₁ and R₂ represent, independently of one another, a hydrogen atom,    a C₁–C₇ alkyl radical, a C₁–C₇ alkoxy radical, a halogen or a    trifluoromethyl group;-   R₃ represents a hydrogen atom or a C₁–C₇ alkyl radical;-   X and Y represent, independently of one another, a sulfur or oxygen    atom;-   R′₁ and R′₂, which are identical or different, represent a C₁–C₇    alkoxy radical;-   n=0 or 1; m and m′, independently of one another,=0, 1 or 2, the sum    n, m and m′=1, 2 or 3;    are claimed in patent EP 481 920 as calcium exchange regulators.

1,5-Benzoxathiepine derivatives of formula:

are described in Steroids, 1998, 63(12), 672 and 1996, 61(5), 296 andare used as pharmacokinetic tools.

3-Arylthiopropylamino-3,4-dihydro-2H-1,5-benzoxathiepine derivativeshave never been described as being openers, activators, agonists,modulators, blockers, inhibitors or antagonists of voltage-dependentsodium channels.

Coronary insufficiency, which encompasses various pathologies (e.g.silent ischemia, stable angina, unstable angina, myocardial infarction,and the like), constitutes one of the main causes of morbidity andmortality in the industrialized world. The aging of the populationshould further contribute to aggravating the situation in the years tocome (Nature Medecine, 1998, 4, 1241). In coronary insufficiency, thecondition of the contractile function is the main determinant of theprognosis. In point of fact, the attack on the contractile function canonly be limited by treatments which preserve the viability of thecardiomyocytes in the region compromised by the ischemia.

Two principles make it possible to postpone the death of the cardiaccells exposed to the ischemia and thus to limit the subsequent degree ofdysfunction:

-   -   rapid reoxygenation of the tissue;    -   maintenance of the ionic homeostasis of the cells.

While, on the one hand, the progress achieved in blood clot therapy andin cardiac surgery have had a positive impact, quantifiable in terms ofclinical benefits (Lancet, 1994, 343, 311; Arch. Intern. Med., 1996,156, 1382), on the other hand, the contribution made by cytoprotectiveagents per se is currently virtually nonexistent (Scrip Magazine,November 1998, p. 15).

This is because the medicaments used in coronary insufficiency (e.g.,beta-blockers, calcium inhibitors, nitro derivatives) all actindirectly, mainly by a hemodynamic phenomenon. Thus, nitro derivativesact by venous and coronary vasodilation, beta-blockers reduce the heartrate and thus cardiac work and calcium channel inhibitors improvecardiac perfusion. Nicorandil, which is both a nitrate and an activatorof ATP-dependent potassium channels, is a vasodilator and reducescardiac work (Eur. Heart J., 1999, 20, 51; Drugs, 2000, 60(4), 955).Trimetazidine has vasodilating effects and acts on the energy metabolismof cells exposed to ischemia (Dictionnaire Vidal®, 74th edition, p.1940, 1998).

It follows that medicaments capable of directly protecting the cardiaccell in a situation of ischemia (chronic or acute) and therefore ofcontributing to preserving the cardiac function in the absence of asignificant hemodynamic effect are highly desirable.

The mechanisms involved in cell death and those which oppose therecovery of the cardiac function after the reestablishment of the bloodcirculation are many and complex. This is because their relativecontributions vary over time and their effects are additive.Nevertheless, it is accepted that myocardial ischemia disrupts, interalia, the operation of the sodium channels and of the Na⁺/K⁺ pump. Thelatter constitutes the main mechanism for the expulsion of Na⁺ ions incardiac cells (J. Mol. Cell Cardiol., 1998, 30, 337). These combinedeffects are probably involved in the intracellular accumulation ofsodium ions observed during ischemia (Circ. Res., 1999, 84, 1401). Thisintracellular accumulation of sodium ions induces, via thesodium-calcium exchanger, a calcium overload already during the ischemicepisode and which is further enhanced during the reperfusion process(Circulation, 1994, 90, 391; J. Mol. Cell. Cardiol., 2000, 32, 1169).The excessive rise in the intra-cellular concentration of calcium ionreduces the contractility and weakens the cytoskeleton. A contractioncan result therefrom and can lead to the death of the cardiac cell.Furthermore, the contraction of a cell can damage the adjacent cells andfurther extend the region of necrosis inside the tissue (Circ. Res.,1999, 85, 280; News Physiol. Sc., 2000, 15, 326). The detrimental changein the contractile function of the exposed cardiac cells is reflectedoverall by a detrimental change in the cardiac function.

In view of the major role played by the sodium overload in theinitiation of processes resulting in the death of the cardiac myocyte,numerous compounds targeted at preventing it have been described(Pharmacol. Res., 1999, 39, 169). Currently, two different routes ofentry of sodium ions into the cell are the subject of attempts attherapeutic interventions: the voltage-dependent sodium channel and thesodium-proton exchanger, although the role of the latter during theischemic episode is disputed (J. Mol. Cell. Cardiol., 1998, 30, 829;Circulation, 2000, 102, 1977; J. Mol. Cell Cardiol., 2000, 32, 1897).The Na⁺/HCO₃ ⁻ co-transporter constitutes a third route of entry of Na⁺ions into the cell but its contribution during ischemia is currentlyunknown (Am. J. Physiol., 1999, 276, C576).

Several inhibitors of the sodium-proton exchanger are described, suchas, for example, the compounds FR 183998 and FR 168888 (Fujisawa),SM-20550 (Sumitomo), KB-R9032 (Organon), MS-31-038 (Mitsui), EMD-96785(Merck KgaA), cariporide (Aventis), TY-12533 (Eur. J. Pharmacol., 2000,404, 221), BIIB-513 (Am. J. Physiol., 2000, 279, H1563) and those whichare subjects of the international applications WO 99/43663, WO 99/61414and WO 99/55690. However, the clinical benefit of this class ofcompounds in coronary diseases remains to be confirmed (Circulation,2000, 102, 3032).

Voltage-dependent sodium channel blockers, for their part, have formedthe subject of intense research for several decades. A large number ofcompounds are consequently available. The latter can be divided intothree main subclasses according to their mode of interaction with thesodium channels.

The first subclass combines together class I antiarrhythmics, localanesthetics and some anticonvulsants (Trends in Pharmacological Science,1992, 13, 352). Several representatives of this subclass are availableclinically. Class I antiarrhythmics, local anesthetics and someanticonvulsants, such as, for example, lidocaine, phenytoin, flecainideand quinidine, have a common site of interaction at the cardiac andneuronal sodium channels (Proc. Natl. Acad. Sci. USA, 1996, 93, 9270).Nevertheless, these agents exert no or exert only a slight cardiaccytoprotective activity. Furthermore, their use in the treatment ofcoronary diseases presents a high risk of side effects. This is becauseit has been shown clinically that compounds such as encainide andflecainide have a high arrhythmogenic potential when theelectrophysiological conditions are detrimentally affected, such as, forexample, during ischemia (Am. J. Cardiol., 1996, 7 (supp. 4A); 12).

The second subclass comprises blockers or modulators of neuronal sodiumchannels which do not appear to significantly affect cardiacvoltage-dependent sodium channels. The compounds belonging to thissubclass are mainly claimed for the treatment of diseases and disordersof the central and/or peripheral nervous system (Exp. Opin.Pharmacother., 1999, 1, 61; Brain Res. Rev., 1998, 26, 16; Trends inPharmacological Science, 1995, 16, 309). This subclass combines togethercompounds of various chemical categories (Ion Channel Modulator, 1997,12, 594; Annual Reports in Medicinal Chemistry, 1998, 33, 51; J. Med.Chem., 2001, 44, 115), M50463 (Brain Res., 1999, 815, 131), NS-7(Naunyn-Schmiedeberg's Arch. Pharmacol., 1997, 355, 601), T-477 (Eur. J.Pharmacol., 2000, 398(2), 209), SUN N8075 (J. Med. Chem., 2000, 43,3372), certain arylpiperidine derivatives (Bioorg. Med. Chem. Lett.,1999, 9, 2999), certain arylpiperidinopropanol derivatives (WO99/23072), certain piperidinol derivatives (WO 00/61558), certainpyrazine derivatives (WO 98/38174), certain N,N-diarylguanidinederivatives (J. Med. Chem., 1998, 41, 3298), certain benzoylguanidinederivatives (EP 822 182), certain sulfonylcyanamide derivatives (DE19820064 and DE 19804251), certain 4-aminopyridine derivatives (DrugDev. Res., 1998, 44, 8), certain 3-aminopyrrole derivatives (J. Med.Chem., 1998, 41, 63), certain aryl(aromatic heterocycle) derivatives (WO00/57877), certain 5-naphth-1-yl-1,3-dioxane derivatives (WO 98/55474),certain chroman derivatives (WO 98/47889), certain cyclic etherderivatives (WO 98/08842), certain quinone derivatives (WO 97/07109),certain derivatives of heterocycles substituted by diphenyl groups (DE19816880), certain benzomorphan derivatives (DE 19740110) and certainbenzindole derivatives (DE 19834714). The advantage of these derivativesas cardiac cytoprotective agents appears to be limited.

The third subclass comprises compounds which act at the cardiac sodiumchannels but via a different mechanism from that of class Iantiarrhythmic agents. This is because they block the noninactivatedsodium channel and thus reduce the slow inactivation component of thesodium current. This is the case with the derivative R 56865, originallydeveloped as antianoxic/antihypoxic agent (EP 0 184 257), thecardioprotective action of which via the voltage-dependent sodiumchannel was only revealed subsequently (J. Cardiovasc. Pharmacol., 1998,31, 800). Other derivatives, claimed inter alia as cardiaccytoprotective agents, might form part of this subclass. They are, forexample, the derivative CRE-319M2 (Naunyn-Schmiedeberg's Arch.Pharmacol., 1998, 358 (supp. 2), 508), 1-cis-diltiazem (Eur. J.Pharmacol., 2000, 391, 217), KC 12291 (Naunyn-Schmiedeberg's Arch.Pharmacol., 1998, 358, 554), CP-060S (J. Cardiovasc. Pharmacol., 1999,33, 70), ST-6 (Drug Data Report, 2000, 22, 790), the benzofuranonesdisclosed in international application WO 96/12718, thebenzo(thia/oxa)zines disclosed in international applications WO 97/05134and WO 00/43391, and the arylisothioureas disclosed in internationalapplication WO 00/43011.

However, although the compounds belonging to the third subclass exhibita high potential as cardiac cytoprotective agents, none is entirelysatisfactory:

-   -   either because of their inadequate selectivity with regard to        the other voltage-dependent ion channels, in particular the K⁺        and/or Ca⁺⁺ channels;    -   or because of their inadequate selectivity with regard to        neuronal and/or (skeletal and/or smooth) muscle        voltage-dependent sodium channels;    -   or because of their inadequate selectivity with regard to the        fast inactivation component of the sodium current;    -   or because of their interaction with other receptor and/or        enzyme systems.

The development of novel molecules, belonging to the third subclass butmore selective than the prior molecules, is therefore highly desirable.

In point of fact, the inventors have discovered, surprisingly, thatcompounds derived from3-aryl-thiopropylamino-3,4-dihydro-2H-1,5-benzoxathiepine canspecifically oppose the sodium overload induced by ischemia by actingdirectly and selectively on the noninactivated voltage-dependent sodiumchannel. Such compounds, capable of alleviating the sodium overloadinduced by ischemia, are cytoprotective and therefore cardioprotectiveoverall and, for this reason, are potentially of use in the treatment ofdiseases related to a sodium overload, in particular coronaryinsufficiency, for which there exists a great therapeutic need.

A subject matter of the present invention is thus a novel family ofcompounds which correspond to the general formula (1)

in which

-   R₁ and R₂, which are identical or different, represent:    -   a hydrogen atom;    -   a fluorine atom or a chlorine atom;    -   a hydroxyl group;    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms;    -   a cyclopropyl radical;    -   a cyclopropoxy radical; or    -   when the R₁ and R₂ groups occupy adjacent positions on the        aromatic ring, then they form, with the carbon atoms which carry        them, a nonaromatic five-membered oxygen-comprising heterocycle        or carbonaceous ring;-   R₃ represents:    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms;    -   a hydroxyl group or a methoxy radical;-   R₄ represents:    -   a hydrogen atom or a methyl radical; and-   R₅ and R₆, which are identical or different, represent:    -   a hydrogen atom;    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkoxy radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkylthio radical including from 1 to 3        carbon atoms;    -   an alkylamino radical;        provided that, when R₄ represents a methyl radical, then R₅        represents a hydrogen atom, an alkoxy radical including from 1        to 3 carbon atoms, a linear or branched alkylthio radical        including from 1 to 3 carbon atoms or an alkylamino radical, or        the OR₄ and R₅ groups form, with the carbons which carry them, a        nonaromatic five- or six-membered heterocycle comprising at        least one oxygen atom, and R₆ is as defined above,        their addition salts and the hydrates of these addition salts        with inorganic acids or organic acids pharmaceutically        acceptable,        and their tautomeric forms, the enantiomers and the mixtures of        enantiomers, and the stereoisomers, pure or as a racemic or        nonracemic mixture.

A more particular subject matter of the invention is derivatives offormula (1) in which:

-   R₁ and R₂, which are identical or different, represent:    -   a hydrogen atom;    -   a fluorine atom or a chlorine atom;    -   a hydroxyl group;    -   an alkyl radical chosen from the group comprising the methyl,        ethyl, propyl and isopropyl radicals;    -   a cyclopropyl radical;    -   an alkoxy radical chosen from the group comprising the methoxy,        ethoxy, propoxy and isopropoxy radicals;    -   a cyclopropoxy radical; or    -   when the R₁ and R₂ groups occupy adjacent positions on the        aromatic ring, then R₁R₂ represent —CH₂CH₂CH₂—, —OCH₂CH₂—,        —OCH₂O— or —CH₂CH₂O—;-   R₃ represents;    -   an alkyl radical chosen from the group comprising the methyl,        ethyl, propyl and isopropyl radicals;    -   a hydroxyl group or a methoxy radical;-   R₄ represents:    -   a hydrogen atom or a methyl radical; and-   R₅ and R₆, which are identical or different, represent:    -   a hydrogen atom;    -   an alkyl radical chosen from the group comprising the methyl,        ethyl and isopropyl radicals;    -   an alkoxy radical chosen from the group comprising the methoxy,        ethoxy, propoxy and isopropoxy radicals;    -   an alkylthio radical chosen from the group comprising the        methylthio, ethylthio and isopropylthio radicals;    -   an alkylamino radical chosen from the group comprising the        N-methylamino and N,N-dimethylamino radicals; or-   R₄R₅ represents a radical chosen from the group comprising —CH₂CH₂—,    —CH₂O—, —CH₂CH₂O—, —CH₂CH₂S— and —CH₂CH₂NR₄—, and R₆ is as defined    above,    their addition salts and the hydrates of these addition salts with    inorganic acids or organic acids pharmaceutically acceptable,    and their tautomeric forms, the enantiomers and the mixtures of    enantiomers, and the stereoisomers, pure or as a racemic or    nonracemic mixture.

In a specific embodiment of the invention, derivatives of formula (1)are chosen from the group comprising:

-   3-[3-(2-methoxyphenylthio)-2-methoxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-methoxyphenylthio)-2-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxyphenylthio)-2-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-methoxyphenylthio)-2-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-methoxyphenylthio)-2-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-methoxyphenylthio)-2-(n-propyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-methoxyphenylthio)-2-(isopropyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-methoxyphenylthio)-2-methylpropyl]amino-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-methoxyphenylthio)-2-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-3-methylphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxyphenylthio)-2-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-3-ethylphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2,3-dihydrobenzofuran-7-thio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-3-methylphenylthio)-2-ethylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-3-methylphenylthio)-2-(isopropyl)-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-3-methylphenylthio)-2-methylpropyl]-amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-3-methoxyphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2,3-dimethoxyphenylthio)-2-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-3-(isopropyl)phenylthio)-2-methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-[3-(2-hydroxy-6-methylphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine,    their addition salts and the hydrates of these addition salts with    inorganic acids or organic acids pharmaceutically acceptable,    and their tautomeric forms, the enantiomers and the mixtures of    enantiomers, and the stereoisomers, pure or as a racemic or    nonracemic mixture.

The compounds of general formula (1) can exist in several tautomericforms. Such tautomeric forms, although not explicitly mentioned in thepresent application in order to simplify the graphical representation ofthe expanded formulae, are nevertheless included in the field ofapplication of the invention.

The compounds of the invention comprise two asymmetric carbon atoms intheir structure. For this reason, they exist in the form of enantiomersand of diastereoisomers. The invention relates both to each purestereoisomer, that is to say associated with less than 5% of anotherstereoisomer or of a mixture of other stereoisomers, and to the mixtureof one or more stereoisomers in all proportions. The compounds of theinvention can therefore participate as pure stereoisomers or racemic ornonracemic mixtures of stereoisomers. However, among the four existingstereoisomers of a compound of formula (1), the enantiomer in which theC(3) asymmetric carbon atom of the 3,4-dihydro-2H-1,5-benzoxathiepinefragment has the (R) absolute configuration and in which the asymmetriccarbon atom which carries the R₃ group has the (S) absoluteconfiguration is, in all cases, preferred.

The labels R and S used to specify the absolute configuration of thestereogenic carbon atoms present in the molecules of formula (1) aredefined as in the Cahn-Ingold-Prelog priority rule (E. L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds, 1994, John Wiley & SonsInc., chap. 5, 104–12).

In another specific embodiment of the invention, the derivatives ofgeneral formula (1) have the (R) absolute configuration at the C(3)asymmetric carbon atom of the 3,4-dihydro-2H-1,5-benzoxathiepinefragment and the (S) absolute configuration at the asymmetric carbonatom which carries the R₃ group.

In another particularly advantageous embodiment of the invention, thederivatives of general formula (1) are chosen from the group comprisingthe following stereoisomers:

-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methoxypropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-hydroxypropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxyphenylthio)-2-(S)-hydroxypropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-(n-propyl)propyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-(isopropyl)-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]-amino-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]-amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxyphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-3-ethylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2,3-dihydrobenzofuran-7-thio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-(isopropyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-3-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2,3-dimethoxyphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-3-isopropylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;-   3-(R)-[3-(2-hydroxy-6-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine,    their addition salts and the hydrates of these addition salts with    inorganic acids or organic acids pharmaceutically acceptable,    and their tautomeric forms, the enantiomers and the mixtures of    enantiomers, and the stereoisomers, pure or as a racemic or    nonracemic mixture.

The invention also relates to the addition salts and optionally thehydrates of the addition salts of the compounds of general formula (1)with inorganic acids or organic acids pharmaceutically acceptable.

The invention also applies to the process for the preparation of thederivatives of general formula (1).

The chemical process used for the preparation of the compounds ofgeneral formula (1) depends on the nature of the R₃ and R₄ substituents.

The compounds of formula (1) can be obtained by one of the processes(a), (b) or (c) described in the following scheme A [lacuna] isillustrated in appendix 1.

Scheme A

According to process (a), when the R₃ radical is other than a hydroxylgroup and R₄ represents a methyl group: the compound of formula (1) isprepared by reductive amination of the aldehyde of formula (II) by meansof a primary amine of formula (I) or of a salt of the primary amine offormula (I). The aldehyde of formula (II) can be isolated before beingcharged to the reductive amination reaction or can be charged to thereductive amination reaction without being isolated beforehand. Thereducing agent used in the reductive amination reaction in question canbe a simple or complex borohydride, such as, for example, sodiumborohydride, potassium borohydride, sodium cyanoborohydride or sodiumtriacetoxyborohydride.

According to process (b), when R₃ is a hydroxyl group: the compound offormula (1) is prepared by regioselective opening of the epoxide offormula (III) by means of the appropriate arylthiophenol of formula (IV)(Synth. Commun., 1996, 26(23), 4459). The epoxide of formula (III) isitself obtained from a precursor of the3-[(1-chloro-2-hydroxypropyl)amino]-3,4-dihydro-2H-1,5-benzoxathiepinetype not mentioned in scheme A as it is not isolated. This is becausethe inventors have discovered that it is experimentally moreadvantageous not to isolate the intermediate in question but to carryout the following intramolecular cyclization stage in situ and toisolate pure only the epoxide of formula (III). Said epoxide (III)results from the reaction between the primary amine of formula (I) and acommercially available epichlorohydrin according to conventionaltechniques of organic chemistry (J. Org. Chem., 1990, 55(9), 2920; WO00/48987). Under the experimental conditions used by the inventors, thenucleophilic attack of the amine of formula (I) on the epichlorohydrinis both chemo- and regioselective.

According to process (c), when R₃ is other than a hydroxyl group and R₄is a hydrogen atom: the intermediate compound of formula (VI) isprepared from the amine of formula (I) and from the aldehyde of formula(V) according to a process identical to that described in process (a). Astage of deprotection of the phenol functional group of the compound(VI) subsequently makes it possible to result in the expected compoundof formula (I) (Eur. J. Org. Chem., 2000, 18, 3223).

The compounds of formula (I) can be purified by one or more methodschosen from liquid-phase chromatography techniques. They cansubsequently, if desired, be salified by means of a pharmacologicallyacceptable organic or inorganic acid.

The preparation of the primary amines of formula (I) is described in thefollowing scheme B which is illustrated in appendix 2.

Scheme B

The intermediate of the N-Boc-(2-hydroxyphenyl)cysteine type (VIII) isprepared in a similar way to that of theN-Boc-(4-hydroxyphenyl)-L-cysteine disclosed in internationalapplication WO 00/20441. The carboxylic acid functional group of thecompound of formula (VIII) is subsequently converted to a primaryalcohol functional group. This reaction can advantageously carried outby reduction of an intermediate mixed anhydride, formed in situ, using asimple or complex borohydride according to a one-pot technique wellknown to the organic chemist. The primary alcohol of formula (IX) issubsequently cyclized, for example by means of an intramolecularMitsunobu reaction, to give the corresponding cyclic compound (X). Theprimary amine of formula (I) is obtained by cleavage of thetert-butoxycarbonyl group using a protic acid, such as, for example,trifluoroacetic acid (T. W. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 1999, John Wiley & Sons Inc., 3rd ed., chap. 7,518–25). The primary amine of formula (I) can, if desired, be salifiedand stored in the hydrochloride or hydro-bromide form, which iscrystalline, nonhygroscopic and stable under standard temperature andlight conditions.

The chemical process used for the preparation of the aldehydes ofgeneral formulae (II) and (V) depends on the nature of the R₃ and R₄substituents.

The aldehydes of formulae (IIa) and (Va), specific cases of thecompounds of formulae (II) and (V) in which R₃ is a methoxy group, canbe prepared according to the method described in the following scheme Cwhich is illustrated in appendix 3.

Scheme C

The primary alcohol functional group of the inter-mediate of the3-arylthio-1,2-propanediol type (XI), prepared in a similar way to thatdisclosed in patent FR 1 064 619, is protected in the trityl ether formaccording to a method analogous to that described by Kim (J. Org. Chem.,1992, 57 (5), 1605). The secondary alcohol functional group of thecompound of formula (XII), activated in the form of an alkali metalalkoxide, is then methylated using a methyl halide or methyl sulfate togive the corresponding compound of formula (XIII). The primary alcoholfunctional group of the compound of formula (XIII) is subsequentlyreleased by hydrolysis of the triphenylmethyl group in protic acidicmedium (T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 1999, John Wiley & Sons Inc., 3rd ed., chap. 2, 102–4).

According to route (a), when R₄ is a methyl radical, the aldehyde offormula (IIa) is obtained by oxidation of the primary alcohol of formula(XIV). The reaction in question can be carried out using an activateddimethyl sulfoxide derivative, such as, for example, dimethyl sulfoxideactivated by the sulfur trioxide-pyridine complex, dimethyl sulfoxideactivated by oxalyl chloride or dimethyl sulfoxide activated by anoxidizing agent of the hypervalent iodine type, such as, for example,the Dess-Martin reagent, according to conventional techniques well knownto the organic chemist.

With regard to the intermediate of formula (XIII), when the R radicalrepresents a methoxymethyl (MOM) group, the detritylation in acidicmedium of the primary alcohol functional group is accompanied by thehydrolysis of the methoxymethyl (MOM) group carried by the phenolfunctional group. The compound obtained is therefore, in this case, thedihydroxylated derivative (XIV, R₄=H). The phenol functional group ofsaid intermediate (XIV, R₄=H) must be protected before carrying out theoxidation of the primary alcohol functional group according to route(b). This is carried out by chemoselective alkylation of the phenolfunctional group using chloromethyl methyl ether according to anexperimental procedure identical to that described in J. Org. Chem.,1998, 63(10), 3260. The oxidation of the primary alcohol (XV) to thealdehyde of formula (Va) is subsequently carried out in a similar way tothat used for the oxidation of the alcohol (XIV, R₄=CH₃) to the aldehyde(IIa), cf. route (a).

The preparation of the aldehydes of formulae (II) and (V) in which theR₃ radical represents an alkyl group, in particular that of thealdehydes of formulae (IIb–g) and (Vb–j), is described in the followingscheme D which is illustrated in appendix 4.

Scheme D

The aldehydes of formulae (IIb–g) and (Vb–j) derive from a commonprecursor of the 2-alkyl-3-(arylthio)propan-1-ol type of formula (XX).This intermediate is obtained by reaction of the appropriate arylthiolof formula (IV) or of an alkali metal salt derived from said arylthiolwith commercially available 3-bromo-2-methylpropan-1-ol or with2-alkyl-3-hydroxypropyl p-toluenesulfonate of formula (XIX), the methodof preparation of which is described hereinafter.

The compound of formula (XVI), prepared according to the methoddescribed by Fukumoto in J. Org. Chem., 1996, 61(2), 677, is reduced tothe alcohol (XVII) using lithium borohydride in tetrahydrofuran (THF)according to an experimental procedure similar to that described in J.Org. Chem., 1994, 59(18), 5317 or in Synth. Commun., 1990, 20(2), 307.The primary alcohol functional group of the compound of formula (XVII)is first converted to the p-toluenesulfonic acid ester (tosylate) offormula (XVIII). The compound of formula (XVIII) can then bedebenzylated by hydrogenolysis in the presence of a palladium catalystto give the expected compound (XIX) according to a method similar tothat described in J. Am. Chem. Soc., 1999, 121(43), 9967.

According to route (a), the intermediate of formula (XX), in which R₄ isa methyl radical or forms, with the adjacent R₅ group, a heterocycle,can be oxidized directly to the aldehyde of formula (II) according to amethod similar to that described above for the oxidation of the alcohol(XIV, R₄=CH₃) to the aldehyde (IIa) (cf. scheme C, route (a)). However,in the case where the enantiomeric purity of the asymmetric carbon atomwhich carries the R₃ radical in the precursor of formula (XX) has to beretained in the final compound of formula (1), the following limitationsapply:

-   -   the reaction for the oxidation of the alcohol (XX) to the        aldehyde (II) is carried out according to the Swern method        modified according to Evans (J. Am. Chem. Soc., 1993, 115(24),        11446);    -   the aldehyde of formula (II) is not isolated but is used in situ        in the following reductive amination stage (cf. scheme A,        process (a)).

According to route (b), the phenol functional group of the compound offormula (XX) is converted either to the methoxymethyl ether (XXIa,R=MOM) or to the methyl ether (XXIb, R=CH₃). The oxidation of thealcohol (XXI) to the aldehyde (II) or (V) is subsequently carried outaccording to a method identical to that used for the preparation of thealdehyde (II) from the alcohol (XX) (cf. scheme D, route (a)). Thelimitations which apply to the oxidation of the alcohol (XX) to thealdehyde (II) and to the use of said aldehyde in the following reductiveamination reaction also apply to the oxidation of the alcohol (XXI) tothe aldehyde (II) or (V) and to their use in the reductive aminationreaction.

The compounds of the arylthiol type of formula (IV), of use asintermediates in the preparation of the aldehydes of formulae (II) and(V) and in the preparation of certain primary amines of formula (I), areeither commercially available or are described in the literature (i.e.Heterocycles, 1999, 50(2), 681; J. Heterocyclic Chem., 1998, 35(3), 699;JP 08143533; JP 06293640; Synth. Commun., 1994, 24(1), 35; J. Org.Chem., 1994, 59(16), 4618; Drug Metab. Dispos., 1992, 20(5), 688; J.Org. Chem., 1990, 55(9), 2736; J. Med. Chem., 1990, 33(5), 1491; J. Med.Chem., 1989, 32(10), 2399; EP 200 212; J. Org. Chem., 1979, 44(26),4971; J. Pharm. Sci., 1976, 65(10), 1554; DE 2411826; Gazz. Chim. Ital.,1969, 99(11), 1095; Gazz. Chim. Ital., 1969, 99(4), 397; J. Am. Chem.Soc., 1955, 77, 568) or are prepared according to the proceduresdescribed in the examples illustrating the present invention.

Another subject matter of the invention is the amines of formula (I)

in which

-   R₁ and R₂, which are identical or different, represent:    -   a hydrogen atom;    -   a fluorine atom or a chlorine atom;    -   a hydroxyl group;    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms;    -   a cyclopropyl radical;    -   a linear or branched alkoxy radical including from 1 to 3 carbon        atoms;    -   a cyclopropoxy radical; or    -   when the R₁ and R₂ groups occupy adjacent positions on the        aromatic ring, they form, with the carbon atoms which carry        them, a nonaromatic five-membered oxygen-comprising heterocycle        or carbonaceous ring;        of use as intermediates in the synthesis of the compounds of        formula (1).

In a particularly advantageous embodiment of the invention, the aminesof formula (1) are those in which the C(3) asymmetric carbon atom hasthe (R) absolute configuration.

Another subject matter of the invention is the process for thepreparation of the compounds of formula (I), characterized in that theN-Boc-(2-hydroxyphenyl)-cysteine of formula (VIII)

is converted to the primary alcohol of formula (IX)

by reduction of an intermediate mixed anhydride, formed in situ, using asimple or complex borohydride according to a one-pot technique,and then said compound (IX) is cyclized to produce the correspondingcyclic compound (X)

which is treated with a protic acid to produce the amine of formula (I),which is salified, if desired.

Another subject matter of the invention is the aldehydes of formula (II)

in which

-   R₃ represents    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms or a methoxy radial,-   R₄ represents:    -   a hydrogen atom or a methyl radical, and-   R₅ and R₆, which are identical or different, represent:    -   a hydrogen atom;    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkoxy radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkylthio radical including from 1 to 3        carbon atoms;    -   an alkylamino radical,        provided that, when R₄ represents a methyl radical, then R₅        represents a hydrogen atom, an alkoxy radical including from 1        to 3 carbon atoms, a linear or branched alkylthio radical        including from 1 to 3 carbon atoms or an alkylamino radical, or        the OR₄ and R₅ groups form, with the carbons which carry them, a        nonaromatic five- or six-membered heterocycle comprising at        least one oxygen atom, and R₆ is as defined above,        of use as intermediates in the synthesis of the compounds of        formula (1).

In a specific embodiment of the invention, the aldehydes of formula (II)are those in which the asymmetric carbon atom carrying the R₃ group hasthe (S) absolute configuration.

Another subject matter of the invention is the aldehydes of formula (V)

in which

-   R₃ represents    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms or a methoxy radical, and-   R₅ and R₆, which are identical or different, represent:    -   a hydrogen atom;    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkoxy radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkylthio radical including from 1 to 3        carbon atoms;    -   an alkylamino radical,        of use as intermediates in the synthesis of the compounds of        formula (1).

In an advantageous embodiment of the invention, the aldehydes of formula(V) are those in which the asymmetric carbon atom carrying the R₃ grouphas the (S) absolute configuration.

Another subject matter of the invention is the process for thepreparation of the compounds of formula (IIa) in which R₃ represents amethoxy group and of the compounds of formula (Va) in which R₃represents a methoxy group, characterized in that the primary alcoholfunctional group of the intermediate of the 3-arylthio-1,2-propanedioltype (XI)

in which R represents a methyl or methoxymethyl (MOM) radical and R₅ andR₆ are as defined in claim 1, is protected in the form of the tritylether of formula (XII),

activated in the form of an alkali metal alkoxide and then methylatedusing a methyl halide or sulfate to give the compound of formula (XIII)

in which R is as defined above, and the primary alcohol functional groupis released by hydrolysis of the triphenylmethyl group in a proticacidic medium, and the following compounds are obtained,

-   -   when R is a methyl radical, a compound of formula (XIVa1)

-   -    the primary alcohol of which is oxidized and a compound of        formula (IIa) is obtained

-   -   when R is a methoxymethyl radical, a compound of formula (XIVa2)        is obtained

-   -    the phenol functional group of which is protected by        chemoselective alkylation using chloromethyl methyl ether and a        compound of formula (XV) is obtained

-   -    the primary alcohol of which is oxidized and a compound of        formula (Va) is obtained

Another subject matter of the invention is the process for thepreparation of the compounds of formulae (II) and (V), in particular ofthe compounds of formula (IIb–g) and of the compounds of formula (Vb–j),in which R₃ represents an alkyl radical, characterized in that

-   -   either a compound of formula (XVI)

-   -    in which R₃ represents a linear or branched alkyl radical        including from 1 to 3 carbon atoms, is reduced and an alcohol of        formula (XVII)

-   -    is obtained, which is converted to a p-toluenesulfonic acid        ester (tosylate) of formula (XVIII)

-   -    which is subjected to hydrogenolysis in the presence of a        palladium catalyst to give the compound (XIX)

-   -    which is reacted with a compound of formula (IV), optionally in        the form of an alkali metal salt,

in which

-   R₄ represents:    -   a hydrogen atom or a methyl radical, and-   R₅ and R₆, which are identical or different, represent:    -   a hydrogen atom;    -   a linear or branched alkyl radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkoxy radical including from 1 to 3 carbon        atoms;    -   a linear or branched alkylthio radical including from 1 to 3        carbon atoms;    -   an alkylamino radical,-    provided that, when R₄ represents a methyl radical, then R₅    represents a hydrogen atom, an alkoxy radical including from 1 to 3    carbon atoms, a linear or branched alkylthio radical including from    1 to 3 carbon atoms or an alkylamino radical, or-    the OR₄ and R₅ groups form, with the carbons which carry them, a    nonaromatic five- or six-membered heterocycle comprising at least    one oxygen atom, and R₆ is as defined above,    -   or 3-bromo-2-methylpropan-1-ol is reacted with a compound of        formula (IV)    -    and a compound of formula (XX)

-   -    is obtained,    -    then, when R₄ is an alkyl radical or forms, with the adjacent        R₅ group, a heterocycle, the compound of formula (XX) is        oxidized directly to the aldehyde of formula (IIb–g)

-   -    or, when R₄ is a hydrogen atom, then the phenol functional        group of the compound of formula (XX) is converted to the        compound of formula (XXI)

-   -    in which R represents a methoxymethyl radical (XXIa, R=MOM) or        a methyl radical (XXIb, R=CH₃), then the alcohol (XXIa) is        oxidized to the aldehyde (II)

-   -    and the alcohol (XXIb) to the aldehyde (V)

Another subject matter of the invention is the pharmaceuticalcompositions comprising, as active principle, at least one of thederivatives of general formula (1) or one of its addition salts orhydrates of its addition salts in combination with one or more inertpharmaceutical carriers or other pharmaceutically acceptable vehiclesand optionally with another medicament.

The pharmaceutical compositions according to the invention can, by wayof example, be compositions which can be administered orally, nasally,sublingually, rectally or parenterally. Mention may be made, by way ofexample of compositions which can be administered orally, of tablets,hard gelatin capsules, granules, powders and solutions or suspensions tobe taken orally.

The appropriate formulations for the chosen administration form areknown and are described, for example, in: Remington, The Science andPractice of Pharmacy, 19th edition, 1995, Mack Publishing Company.

The effective dose of a compound of the invention varies according tonumerous parameters, such as, for example, the chosen administrationroute, the weight, the age, the sex, the nature of the pathology and thesensitivity of the individual to be treated. Consequently, the optimumdosage should be determined, according to the parameters regarded asrelevant, by a specialist in the matter. Although the effective doses ofa compound of the invention can vary greatly, the daily doses mightrange between 0.01 mg and 100 mg per kg of body weight of the individualto be treated. A daily dose of a compound of the invention of between0.10 mg and 50 mg per kg of body weight of the individual to be treatedbeing preferred, however.

The pharmaceutical compositions according to the invention are of use inthe treatment of stable angina, unstable angina, cardiac insufficiency,long QT syndrome of congenital origin, myocardial infarction and cardiacrhythm disorders.

They can also be of use in the treatment of cerebral ischemia,transitory ischemic attack, neuropathies of a traumatic or ischemicnature, and epilepsy, and in that of the treatments of pain ofneuropathic origin and of neurodegenerative diseases.

EXAMPLES

The following examples illustrate the invention but do not limit it inany way:

-   -   examples 1 to 4 illustrate the synthesis of the intermediates I        according to scheme B,    -   examples 5 and 6 illustrate the synthesis of the intermediates        IIa according to scheme C,    -   examples 7 to 15 illustrate the synthesis of the intermediates        IIb–g according to scheme D,    -   examples 16 and 17 illustrate the synthesis of the intermediates        III of process b illustrated in scheme A,    -   examples 18 to 25 illustrate the synthesis of the intermediates        V according to route c illustrated in scheme D,    -   examples 26 to 34 illustrate the synthesis of the intermediates        VIa–j according to process c illustrated in scheme A, and    -   reference examples 1 to 26 illustrate the synthesis of the        compounds of formula (1) according to scheme A.

In the examples and the reference examples hereinafter:

-   (i) the progress of the reactions is monitored by thin layer    chromatography (TLC) and, consequently, the reaction times are only    mentioned by way of indication;-   (ii) different crystalline forms can give different melting points;    the melting points mentioned in the present application are those of    the products prepared according to the method described and are not    corrected;-   (iii) the structures of the products obtained according to the    invention are confirmed by the nuclear magnetic resonance (NMR)    spectra, the infrared (IR) spectra and percentage analysis, the    purity of the final products is confirmed by TLC, and the    enantiomeric purity of the reaction intermediates and of the final    products is determined by chiral phase HPLC;-   (iv) the NMR spectra are recorded in the solvent indicated. The    chemical shifts (δ) are expressed in parts per million (ppm) with    respect to tetramethylsilane. The multiplicity of the signals is    indicated by: s, singlet; d, doublet; t, triplet; q, quartet; m,    multiplet; b, broad;-   (v) the different symbols for the units have their usual meanings:    μg (microgram); mg (milligram); g (gram); ml (milliliter); mV    (millivolt); ° C. (degrees Celsius); mmol (millimole); nmol    (nanomole); cm (centimeter); nm (nanometer); min (minute); ms    (millisecond); Hz (hertz); [α](specific rotation, measured at 589    nm, at 25° C. and at the concentration c; in the present invention,    the measure deg.cm².g⁻¹ is always to be understood); the pressures    are given in millibar (mb);-   (vi) the abbreviations have the following meanings: M.p. (melting    point); B.p. (boiling point); AUC (area under the curve);-   (vii) the term “ambient temperature” is understood to mean a    temperature between 20° C. and 25° C.

Example 1 3-(R)-Amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1)

Stage 1:2-(R)-tert-Butoxycarbonylamino-3-(2-hydroxyphenylthio)propan-1-ol(IXa-1)

74.45 g (0.237 mol) of N-Boc-(2-hydroxyphenyl)-L-cysteine (VIII) and 300ml of distilled tetrahydrofuran are introduced into a round-bottomedflask kept under an inert atmosphere. The mixture is cooled to −10° C.and then 26 ml (0.236 mol) of N-methylmorpholine are added dropwise.After stirring for 15 minutes at −10° C., 22.7 ml (0.237 mol) of ethylchloroformate are introduced dropwise. The mixture is stirred at −10° C.for 30 minutes and then the precipitate formed is filtered off undercold conditions. The filtrate is recovered directly in a round-bottomedflask and cooled to −10° C. 13.45 g (0.35 mol) of sodium borohydride insolution in 50 ml of water are then introduced in such a way that thetemperature of the mixture does not exceed −10° C. At the end of theaddition, the mixture is reheated to ambient temperature and stirred for12 hours. The mixture is concentrated under reduced pressure, acidifiedusing 250 ml of an aqueous potassium hydrogensulfate solution (2N) andextracted with dichloromethane. The combined organic phases are washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. 61.41 g (0.205 mol) of the title compound (IXa-1) areobtained in the form of a yellow oil, which is used without additionalpurification in the following stage.

Crude yield: 86% [α]=−44.2 (c=0.371, methanol) ¹H NMR (d₆-DMSO) δ: 1.38(s, 9H), 2.80 (dd, 1H), 3.03 (dd, 1H), 3.35 (bs, 1H), 3.49 (m, 2H), 4.78(m, 1H), 6.74 (m, 3H), 7.02 (m, 1H), 7.23 (m, 1H), 9.72 (bs, 1H).

Stage 2:3-(R)-tert-Butoxycarbonylamino-3,4-dihydro-2H-1,5-benzoxathiepine (Xa-1)

[lacuna] (0.205 mol) of2-tert-butoxycarbonyl-amino-3-(2-hydroxyphenylthio)propan-1-ol (IXa-1),300 ml of distilled tetrahydrofuran and 53.80 g (0.205 mol) oftriphenylphosphine are introduced into a round-bottomed flask kept underan inert atmosphere. The mixture is cooled to 0° C. and then 31.9 ml(0.205 mol) of diethyl azodicarboxylate are added dropwise. The mixtureis stirred at ambient temperature for 24 hours. The tetrahydrofuran isevaporated under reduced pressure and then the residue is taken up inethyl ether. The precipitate formed is removed by filtration and thefiltrate is concentrated under reduced pressure. The residue is purifiedby flash chromatography on silica gel (eluent:dichloromethane/cyclohexane=80:20). 48 g (0.170 mol) of the titlecompound (Xa-1) are recovered in the form of a pinkish oil.

Yield: 83% [α]=+15.2 (c=0.493, methanol) ¹H NMR (CDCl₃) δ: 1.47 (s, 9H),2.93 (dd, 1H), 3.07 (dd, 1H), 3.95 (d, 1H), 4.27 (bs, 1H), 4.34 (d, 1H),5.64 (bd, 1H), 7.00 (m, 2H), 7.18 (td, 1H), 7.41 (d, 1H) HPLC (ChiracelOD, hexane/isopropanol (92:8), 0.5 ml/min): compound (Xa-1), retentiontime=12.71 min; compound (Xa-2), retention time=14.05 min; ratio of theAUCs (Xa-1)/(Xa-2)=98:2.

Stage 3: 3-(R)-Amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1)

48 g (0.170 mol) of3-(R)-tert-butoxycarbonyl-amino-3,4-dihydro-2H-1,5-benzoxathiepine(Xa-1) and 120 ml of hydrochloric acid (2N) in ethanol are introducedinto a round-bottomed flask equipped with a reflux condenser. Themixture is brought to 80° C. for 2 to 3 hours. The mixture is cooled,concentrated under reduced pressure and then diluted with ethyl ether.The precipitate formed is filtered off, washed with ethyl ether andpulled dry. 19 g (0.087 mol) of the hydrochloride of the title compound(Ia-1) are thus recovered in the form of a white solid.

Yield: 50% M.p.: 235° C. [α]=+48.9 (c=0.350, methanol) AnalysisC₉H₁₂ClNOS:

Calc. %: C 49.65 H 5.56 N 6.43 Found: C 49.59 H 5.63 N 6.32¹H NMR (d₆-DMSO) δ: 3.12 (dd, 1H), 3.21 (dd, 1H), 3.81 (m, 1H), 4.21(dd, 1H), 4.31 (dd, 1H), 7.09 (m, 2H), 7.28 (td, 1H), 7.45 (dd, 1H),8.64 (bs, exchangeable) HPLC (Chiralpack AD, hexane/ethanol/diethylamine(95:4.95:0.05), 1 ml/min): compound (Ia-1), retention time=25.26 min;compound (Ia-2), retention time=23.48 min; ratio of the AUCs(Ia-1)/(Ia-2)=98:2.

Example 2 3-(S)-Amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-2)

The hydrochloride of the title compound (Ia-2) is prepared according toa reaction sequence identical to that employed for the synthesis of3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1) but using, asstarting material, N-Boc-(2-hydroxyphenyl)-D-cysteine instead ofN-Boc-(2-hydroxyphenyl)-L-cysteine.

M.p. 210° C. (sublimation) [α]=−44.8 (c=0.402, methanol) AnalysisC₉H₁₂ClNOS:

Calc. %: C 49.65 H 5.56 N 6.43 Found: C 49.68 H 5.57 N 6.50¹H NMR (d₆-DMSO) δ: 3.12 (dd, 1H), 3.21 (dd, 1H), 3.80 (bs, 1H), 4.20(d, 1H), 4.31 (dd, 1H), 7.09 (m, 2H), 7.28 (m, 1H), 7.45 (d, 1H), 8.63(bs, exchangeable). HPLC (Chiralpack AD, hexane/ethanol/diethylamine(95:4.95:0.05), 1 ml/min): compound (Ia-2), retention time=23.07 min;compound (Ia-1), retention time=24.99 min; ratio of the AUCs(Ia-2)/(Ia-1)=96:4.

Example 3 3-(R)-Amino-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine (Ib)

The title compound (Ib) is prepared according to a reaction sequenceidentical to that employed for the synthesis of3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1) but using, asstarting material, 2-hydroxy-5-methylthiophenol (IVb) instead of2-hydroxythiophenol. The title compound (Ib) is obtained in the form ofa yellow oil.

Yield: 60% [α]=+46 (c=0.106, methanol) ¹H NMR (CDCl₃) δ: 1.65 (bs,exchangeable H), 2.26 (s, 3H), 2.76 (dd, 1H), 3.15 (dd, 1H), 3.42 (m,1H), 4.05 (m, 2H), 6.92 (m, 2H), 7.19 (d, 1H).

Example 4 3-(R)-Amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine (Ic)

Stage 1: 2-Hydroxy-6-methylthiophenol (IVc)

5.3 g (0.077 mol) of sodium nitrite in solution in 12 ml of water areadded dropwise to a round-bottomed flask comprising 14 g of ice, 14 mlof 36% hydrochloric acid and 8.62 g (0.07 mol) of 2-amino-m-cresol. Themixture, kept at 0° C., is subsequently poured slowly into a solution of15 g (0.093 mol) of potassium ethyl xanthate in 20 ml of water held at40° C. The heating bath is removed and the mixture is stirred for 3hours and then extracted with ethyl ether. The combined organic phasesare washed with aqueous saline solution, dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue ispurified by fast chromatography on silica gel (eluent:cyclohexane/dichloromethane=65:35). The oil obtained is taken up in 20ml of ethanol and the mixture is heated to 100° C. 20 ml of an ethanolicpotassium hydroxide solution (7N) are then added dropwise. After 4 hoursat 100° C., the mixture is cooled, concentrated under reduced pressure,acidified using hydrochloric acid (2N) and then extracted with ethylether. The combined organic phases are dried over magnesium sulfate,filtered and concentrated under reduced pressure to give a yellow oilwhich is not isolated but is used directly in the following stage.

Stage 2: 3-(R)-Amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine (Ic)

The hydrochloride of the title compound (Ic) is prepared according to areaction sequence similar to that employed for the synthesis of3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1) but using, asstarting material, 2-hydroxy-6-methylthiophenol (IVc) instead of2-hydroxythiophenol.

M.p.>250° C. [α]=+101.4 (c=0.313, methanol) Analysis C₁₀H₁₄ClNOS:

Calc. %: C 51.83 H 6.09 N 6.04 Found: C 51.64 H 6.12 N 5.89¹H NMR (d₆-DMSO) δ: 2.37 (s, 3H), 3.16 (m, 2H), 3.79 (m, 1H), 4.20 (1d,1H), 4.30 (dd, 1H), 6.94 (d, 1H), 7.03 (d, 1H), 7.14 (m, 1H), 8.59 (bs,3 exchangeable H).

Example 5 2-(S)-Methoxy-3-(2-methoxyphenylthio)-propionaldehyde (IIa-1)

Stage 1:1-(3-Triphenylmethyloxy-2-(S)-hydroxy-propylthio)-2-methoxybenzene(XII-1)

19.3 g (0.09 mol) of1-(3-hydroxy-2-(S)-hydroxy-propylthio)-2-methoxybenzene (XI-1), 150 mlof acetonitrile, 11 ml (0.136 mol) of pyridine and 27.5 g (0.098 mol) oftriphenylmethyl chloride are introduced into a round-bottomed flaskunder an inert atmosphere. The solution is stirred at ambienttemperature for 5 hours. The mixture is concentrated under reducedpressure and the residual pyridine is entrained by azeotropicdistillation with toluene. The residue is taken up in water and thenextracted with dichloromethane. The combined organic phases are driedover sodium sulfate, filtered and evaporated, and the residue ispurified by flash chromatography on silica gel (eluent:cyclohexane/dichloromethane=30:70). 34.8 g (0.076 mol) of the titlecompound (XII-1) are recovered in the form of a yellow oil.

Yield: 85% [α]=−7.1 (c=0.225, methanol) ¹H NMR (CDCl₃) δ: 2.80 (d, 1H),2.93 (dd, 1H), 3.14 (dd, 1H), 3.23 (d, 2H), 3.77 (m, 1H), 3.87 (s, 3H),6.88 (m, 2H), 7.25 (m, 10H), 7.34 (dd, 1H), 7.41 (d, 6H).

Stage 2:1-(3-Triphenylmethyloxy-2-(S)-methoxy-propylthio)-2-methoxybenzene(XIII-1)

34.8 g (0.076 mol) of1-(3-triphenylmethyloxy-2-(S)-hydroxypropylthio)-2-methoxybenzene(XII-1), in solution in 50 ml of distilled tetrahydrofuran, areintroduced dropwise into a round-bottomed flask, kept under an inertatmosphere, comprising a suspension of 3.5 g of sodium hydride (0.087mol) in 30 ml of distilled tetrahydrofuran. The mixture is stirred atambient temperature for 3 hours and then 5.1 ml (0.082 mol) of methyliodide are added. After stirring at ambient temperature for 2 hours, themixture is concentrated under reduced pressure and then the residue istaken up in dichloromethane. The solution obtained is cooled and thendiluted with ice-cold water. The phases are separated and the aqueousphase is extracted with dichloromethane. The combined organic phases arewashed with water and with brine, dried over magnesium sulfate, filteredand concentrated under reduced pressure. The residue is purified byflash chromatography on silica gel (eluent:dichloromethane/cyclohexane=70:30) to give 35.8 g (0.076 mol) of thetitle compound (XIII-1) in the form of an oil.

Yield: 100% ¹H NMR (CDCl₃) δ: 3.01 (dd, 1H), 3.16 (dd, 1H), 3.25 (dd,2H), 3.36 (s, 3H), 3.43 (m, 1H), 3.85 (s, 3H), 6.86 (m, 2H), 7.41 (m,10H), 7.35 (m, 1H), 7.43 (d, 6H).

Stage 3: 2-(S)-Methoxy-3-(2-methoxyphenylthio)-propan-1-ol (XIV-1)

35.8 g (0.076 mol) of1-(3-triphenylmethyloxy-2-(S)-methoxypropylthio)-2-methoxybenzene(XIII-1) and 150 ml of a solution of hydrochloric acid (2.5N) in ethanolare introduced into a round-bottomed flask kept under an inertatmosphere. The mixture is stirred at ambient temperature for 4 hours.The white precipitate formed is removed by filtration and the filtrateis concentrated under reduced pressure. The residue is purified by flashchromatography on silica gel (eluent: dichloromethane/ethylacetate=90:10). 13.4 g (0.058 mol) of the title compound (XIV-1) arerecovered in the form of an orange oil.

Yield: 77% [α]=−15.5 (c=0.0780, methanol) ¹H NMR (CDCl₃) δ: 1.99 (t,1H), 2.97 (dd, 1H), 3.15 (dd, 1H), 3.42 (s, 3H), 3.44 (m, 1H), 3.65 (m,1H), 3.83 (m, 1H), 3.90 (s, 3H), 6.87 (d, 1H), 6.93 (t, 1H), 7.23 (td,1H), 7.35 (dd, 1H).

Stage 4: 2-(S)-Methoxy-3-(2-methoxyphenylthio)-propionaldehyde (IIa-1)

4 g (0.017 mol) of 2-(S)-methoxy-3-(2-methoxyphenylthio)propan-1-ol(XIV-1), 100 ml of dichloromethane and 11.13 g (0.026 mol) ofDess-Martin reagent are introduced into a round-bottomed flask keptunder an inert atmosphere. The mixture is stirred at ambient temperaturefor 3 hours. 190 ml of a saturated aqueous sodium thiosulfate solutionare subsequently added, followed by 190 ml of a saturated aqueous sodiumhydrogencarbonate solution, and the mixture is extracted withdichloromethane. The combined organic phases are washed with water andwith brine, dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue is purified by flash chromatographyon silica gel (eluent: dichloromethane/ethyl acetate=95:5). 1.2 g (0.005mol) of the title compound (IIa-1) are recovered in the form of a yellowoil.

Yield: 31% ¹H NMR (CDCl₃) δ: 3.13 (dd, 1H), 3.23 (dd, 1H), 3.47 (s, 3H),3.70 (m, 1H), 3.90 (s, 3H), 6.88 (dd, 1H), 6.92 (td, 1H), 7.26 (td, 1H),7.38 (dd, 1H), 9.68 (d, 1H).

Example 6 2-(R)-Methoxy-3-(2-methoxyphenylthio)-propionaldehyde (IIa-2)

The title compound (IIa-2) is obtained by carrying out the preparationas in example 5 but by replacing, in stage 1,1-(3-hydroxy-2-(S)-hydroxypropylthio)-2-methoxybenzene (XI-1) with1-(3-hydroxy-2-(R)-hydroxypropylthio)-2-methoxybenzene (XI-2).

Yield: 90% ¹H NMR (CDCl₃) δ: 3.12 (dd, 1H), 3.23 (dd, 1H), 3.47 (s, 3H),3.70 (m, 1H), 3.90 (s, 3H), 6.89 (m, 2H), 7.26 (m, 1H), 7.38 (dd, 1H),9.67 (d, 1H).

Example 7 2-(S)-Methyl-3-(2-methoxyphenylthio)-propionaldehyde (IIb-1)

Stage 1: 2-(S)-Methyl-3-(2-methoxyphenylthio)-propan-1-ol (XXb-1)

2.2 ml (0.021 mol) of 3-bromo-2-(S)-methyl-1-propanol are introducedinto a round-bottomed flask kept under an inert atmosphere. 20 ml of anaqueous sodium hydroxide solution (1N) are added dropwise, followed by2.3 ml (0.019 mol) of 2-methoxythiophenol. The mixture is brought to 90°C. for 4 hours and is then cooled to ambient temperature. 50 ml of waterare then added and the mixture is extracted with dichloromethane. Thecombined organic phases are washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residueis purified by flash chromatography on silica gel (eluent:dichloromethane/methanol=99:1). 4 g (0.019 mol) of the title compound(XXb-1) are recovered in the form of a colorless oil.

Yield: 100% [α]=+22.2 (c=0.982, methanol) ¹H NMR (d₆-DMSO) δ: 0.95 (d,3H), 1.74 (m, 1H), 2.61 (dd, 1H), 3.01 (dd, 1H), 3.34 (m, 2H), 3.80 (s,3H), 4.61 (t, 1 exchangeable H), 6.94 (m, 2H), 7.14 (td, 1H), 7.23 (dd,1H).

Stage 2: 2-(S)-Methyl-3-(2-methoxyphenylthio)-propionaldehyde (IIb-1)

0.61 ml (0.007 mol) of oxalyl chloride and 20 ml of dichloromethane areintroduced into a round-bottomed flask kept under an inert atmosphere.The mixture is cooled to −78° C. and then 1 ml (0.014 mol) of dimethylsulfoxide is introduced. After stirring at −78° C. for 15 minutes, 1.5 g(0.007 mol) of 2-(S)-methyl-3-(2-methoxyphenylthio)propan-1-ol (XXb-1),in solution in 15 ml of dichloromethane, are added dropwise. The mixtureis stirred at −78° C. for 1 hour and then 2 ml (0.014 mol) oftriethylamine are added. After 15 minutes at −78° C., the mixture isreheated to −10° C. and stirred at this temperature for 45 minutes. Thealdehyde is not isolated at this stage but is used in situ in thefollowing reductive amination reaction.

Example 8 2-(R)-Methyl-3-(2-methoxyphenylthio)-propionaldehyde (IIb-2)

The title compound (IIb-2) is obtained by carrying out the preparationas in example 7 but by using, in stage 1,3-bromo-2-(R)-methyl-1-propanol instead of3-bromo-2-(S)-methyl-1-propanol. This title compound, like the aldehyde(IIb-1) is not isolated but is used in situ in the following reductiveamination reaction.

Example 9 2-(S)-Methyl-3-(2,3-dihydrobenzofuran-7-thio)propionaldehyde(IIc)

Stage 1: 2,3-Dihydrobenzofuran-7-thiol (IVd)

3 ml (0.026 mol) of 2,3-dihydrobenzofuran and 50 ml of ethyl ether areintroduced into an inert atmosphere. The mixture is cooled to 0° C. andthen 11.5 ml (0.029 mol) of a solution of n-butyllithium (2.5M) inhexane are added dropwise. At the end of the addition, the mixture isbrought to reflux for 24 hours and then cooled to 0° C. before adding,portionwise, 0.92 g (0.029 mol) of sublimed sulfur. The mixture isheated at reflux for 2 hours and is then again cooled to 0° C. beforeadding 6 ml of hydrochloric acid (10N). The phases are separated and theaqueous phase is extracted with ethyl ether. The combined organic phasesare washed with an aqueous hydrochloric acid solution (1N) and withwater and then extracted using an aqueous sodium hydroxide solution(1N). The combined alkaline phases are washed with ethyl ether,acidified and extracted with ethyl ether. The combined ethereal phasesare dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue is purified by flash chromatography on silica gel(eluent: cyclohexane/ether=90:10) to give 0.4 g (0.0026 mol) of thetitle compound (IVd).

Yield: 10% ¹H NMR (d₆-DMSO) δ: 3.20 (t, 2H), 4.55 (m, 2H), 4.79 (bs, 1exchangeable H), 6.72 (m, 1H), 7.01 (m, 2H).

Stage 2: 2-(S)-Methyl-3-(2,3-dihydrobenzofuran-7-thio)propionaldehyde(IIc)

The title compound (IIc) is obtained by carrying out the preparation asin example 7 but by using, in stage 1, 2,3-dihydrobenzofuran-7-thiol(IVd) instead of 2-methoxythiophenol. This title compound, like thealdehyde (IIb-1), is not isolated but is used in situ in the followingreductive amination reaction.

Example 10 2-(S)-Ethyl-3-(2-methoxyphenylthio)-propionaldehyde (IId-1)

Stage 1: 2-(R)-Ethyl-3-benzyloxypropan-1-ol (XVIId-1)

3.08 g (0.0084 mol) of4-(R)-benzyl-3-(2-(R)-(benzyloxymethylbutyryl)oxazolidin-2-one (XVId-1),70 ml of ethyl ether and 0.17 ml (0.0092 mol) of water are introducedinto a round-bottomed flask kept under an inert atmosphere. The mixtureis cooled to 0° C. and then 4.6 ml (0.0092 mol) of lithium borohydride(2N) in tetrahydrofuran are added dropwise. The mixture is stirred at 0°C. for 1 hour and then an aqueous sodium hydroxide solution (1N) isintroduced in an amount sufficient for the phases to become clear. Thephases are separated and the aqueous phase is extracted with ethylether. The combined organic phases are washed with water and with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue is purified by flash chromatography on silica gel(eluent: cyclohexane/ethyl acetate=70:30). 1.34 g (0.0069 mol) of thetitle compound (XVIId-1) are obtained in the form of a colorless oil.

Yield: 82% [α]=+21 (c=0.634, CDCl₃) ¹H NMR (CDCl₃) δ: 0.92 (t, 3H), 1.31(m, 2H), 1.80 (m, 1H), 2.59 (m, 1H), 3.48 (t, 1H), 3.63 (m, 2H), 3.73(m, 1H), 4.52 (s, 1H), 4.53 (s, 1H), 7.32 (m, 5H).

Stage 2: 2-(S)-Ethyl-3-benzyloxypropyl p-toluenesulfonate (XVIIId-1)

1.34 g (0.0069 mol) of 2-(R)-ethyl-3-benzyloxypropan-1-ol (XVIId-1), 12ml of dichloromethane, 1.31 g (0.0069 mol) of tosyl chloride and 0.084 g(0.0007 mol) of 4-dimethylaminopyridine are introduced into around-bottomed flask kept under an inert atmosphere. The mixture iscooled to 0° C. and then 0.89 ml (0.011 mol) of pyridine is addeddropwise. After leaving overnight in a refrigerator, the mixture ishydrolyzed using a 10% aqueous citric acid solution. The phases areseparated and the aqueous phase is extracted with ethyl ether. Thecombined organic phases are washed with water and with brine, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue is purified by flash chromatography on silica gel (eluent:dichloromethane/cyclohexane=750:25). 1.54 g (0.0044 mol) of the titlecompound (XVIIId-1) are obtained.

Yield: 64% [α]=+4 (c=0.326, CDCl₃) ¹H NMR (CDCl₃) δ: 0.85 (t, 3H), 1.37(m, 2H), 1.84 (m, 1H), 2.41 (s, 3H), 3.38 (m, 2H), 4.07 (s, 1H), 4.08(s, 1H), 4.38 (s, 2H), 7.28 (m, 7H), 7.78 (d, 2H).

Stage 3: 2-(S)-Ethyl-3-hydroxypropyl p-toluene-sulfonate (XIXd-1)

1.5 g (0.0043 mol) of 2-(S)-ethyl-3-benzyloxypropyl p-toluenesulfonate(XVIIId-1), 12 ml of ethanol and 0.29 g of 20% palladium hydroxide areintroduced into a 100 ml round-bottomed flask. The mixture is vigorouslystirred at ambient temperature under a slight hydrogen pressure. Afterreacting for one hour, the mixture is filtered through celite and thesolid is washed with ethanol. The filtrate is concentrated under reducedpressure and the residue is purified by flash chromatography on silicagel (eluent: dichloromethane/cyclohexane=80:20). 1.02 g (0.0039 mol) ofthe title compound (XIXd-1) are recovered in the form of a colorlessoil.

Yield: 92% [α]=−6.2 (c=0.423, CDCl₃) ¹H NMR (CDCl₃) δ: 0.88 (t, 3H),1.33 (m, 2H), 1.52 (t, 1H), 1.74 (m, 1H), 2.45 (s, 3H), 3.57 (m, 1H),3.65 (m, 1H), 4.05 (dd, 1H), 4.12 (dd, 1H), 7.35 (d, 2H), 7.80 (d, 2H).

Stage 4: 2-(S)-Ethyl-3-(2-methoxyphenylthio)-propan-1-ol (XXd-1)

0.47 ml (0.0038 mol) of 2-methoxythiophenol, in solution in 5 ml ofdimethylformamide, is added dropwise to a round-bottomed flask, keptunder an inert atmosphere, comprising 0.19 g (0.0047 mol) of sodiumhydride in suspension in 10 ml of dimethylformamide cooled to 0° C. Themixture is reheated to ambient temperature and stirred for 1 hour, then0.99 g (0.0038 mol) of 2-(S)-ethyl-3-hydroxypropyl p-toluene-sulfonate(XIXd-1), in solution in 10 ml of dimethyl-formamide, is added. Afterstirring at ambient temperature for 2 hours, the dimethylformamide isevaporated under high vacuum and the residue is taken up indichloromethane. The organic phase is washed with water and with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue is purified by flash chromatography on silica gel(eluent: dichloromethane/methanol=98:2). 0.87 g (0.0038 mol) of thetitle compound (XXd-1) is recovered in the form of an oil.

Yield: 100% ¹H NMR (CDCl₃) δ: 0.94 (t, 3H), 1.49 (m, 2H), 1.74 (m, 1H),1.80 (m, 1H), 2.98 (m, 2H), 3.68 (m, 1H), 3.76 (m, 1H), 3.90 (s, 3H),6.86 (d, 1H), 6.93 (td, 1H), 7.19 (td, 1H), 7.32 (dd, 1H). HPLC(Chiracel OD, hexane/isopropanol (90:10), 1 ml/min): compound (XXd-1),retention time=11.44 min; compound (XXd-2), retention time=13.23 min;ratio of the AUCs (XXd-1)/(XXd-2)=99.9:0.1.

Stage 5: 2-(S)-Ethyl-3-(2-methoxyphenylthio)-propionaldehyde (IId-1)

The title compound (IId-1) is obtained by carrying out the preparationas in example 7 but by replacing, in stage 2,2-(S)-methyl-3-(2-methoxyphenylthio)propan-1-ol (XXb-1) with2-(S)-ethyl-3-(2-methoxy-phenylthio)propan-1-ol (XXd-1). This titlecompound, like the aldehyde (IIb-1), is not isolated but is used in situin the following reductive amination reaction.

Example 11 2-(R)-Ethyl-3-(2-methoxyphenylthio)-propionaldehyde (IId-2)

The title compound (IId-2) is obtained by carrying out the preparationas in example 10 but by replacing, in stage 1,4-(R)-benzyl-3-(2-(R)-(benzyloxymethyl)-butyryl)oxazolidin-2-one(XVId-1) with4-(S)-benzyl-3-(2-(S)-(benzyloxymethyl)butyryl)oxazolidin-2-one(XVId-2). This title compound, like the aldehyde (IId-1), is notisolated but is used in situ in the following reductive aminationreaction.

Example 12 2-(S)-(n-Propyl)-3-(2-methoxyphenylthio)-propionaldehyde(IIe-1)

The title compound (IIe-1) is obtained by carrying out the preparationas in example 10 but by using, in stage 1,4-(R)-benzyl-3-(2-(R)-(benzyloxymethyl)-pentanoyl)oxazolidin-2-one(XVIe-1) instead of4-(R)-benzyl-3-(2-(R)-(benzyloxymethyl)butyryl)oxazolidin-2-one(XVId-1). This title compound, like the aldehyde (IId-1), is notisolated but is used in situ in the following reductive aminationreaction.

Example 13 2-(R)-(n-Propyl)-3-(2-methoxyphenylthio)-propionaldehyde(IIe-2)

The title compound (IIe-2) is obtained by carrying out the preparationas in example 10 but by using, in stage 1,4-(S)-benzyl-3-(2-(S)-(benzyloxymethyl)-pentanoyl)oxazolidin-2-one(XVIe-2) instead of4-(R)-benzyl-3-(2-(R)-(benzyloxymethyl)butyryl)oxazolidin-2-one(XVId-1). This title compound, like the aldehyde (IId-1), is notisolated but is used in situ in the following reductive aminationreaction.

Example 14 2-(S)-Isopropyl-3-(2-methoxyphenylthio)-propionaldehyde (IIf)

The title compound (IIf) is obtained by carrying out the preparation asin example 10 but by using, in stage 1,4-(R)-benzyl-3-(2-(R)-benzyloxymethyl-3-methylbutyryl)oxazolidin-2-one(XVIf) instead of4-(R)-benzyl-3-(2-(R)-(benzyloxymethyl)butyryl)oxazolidin-2-one(XVId-1). This title compound, like the aldehyde (IId-1), is notisolated but is used in situ in the following reductive aminationreaction.

Example 15 2-(S)-Methyl-3-(2,3-dimethoxyphenylthio)-propionaldehyde(IIg)

Stage 1: 2-Mercapto-6-methoxyphenol (IVg)

The compound (IVg) is prepared from guaiacol according to the methodreported by Tanabe (Heterocycles, 1999, 50(2), 681). The crude reactionproduct is taken up in a tetrahydrofuran/water (1:1) mixture and treatedwith 1 equivalent of triphenylphosphine at 60° C. for 2 to 3 hours andthen with an aqueous sodium hydroxide solution (1N). The mixture iswashed with pentane and then with dichloromethane. The aqueous phase isacidified with an aqueous hydrochloric acid solution (1N) and extractedwith ethyl acetate. The ethyl acetate phase is dried over sodiumsulfate, filtered and concentrated under reduced pressure to give ayellow oil which is used without additional purification in thefollowing stage.

¹H NMR (d₆-DMSO) δ: 3.77 (s, 3H), 4.58 (s, 1H), 6.67 (m, 1H), 6.74 (dd,1H), 6.81 (dd, 1H), 9.12 (s, 1H).

Stage 2: 2-(S)-Methyl-3-(2-hydroxy-3-methoxy-phenylthio)propan-1-ol(XXg)

0.57 g of 2-mercapto-6-methoxyphenol (IVg), in solution in 5 ml ofdimethylformamide, is introduced dropwise into a round-bottomed flask,kept under an inert atmosphere, comprising 0.13 g (0.0032 mol) of sodiumhydride and 5 ml of dimethylformamide. After 30 minutes, 0.34 ml (0.0033mol) of bromo-2-(S)-methyl-1-propanol is added and the mixture isstirred at ambient temperature for 5 hours. The mixture is concentratedunder reduced pressure, taken up in an aqueous hydrochloric acidsolution (1N) and extracted with dichloromethane. The combined organicphases are dried over sodium sulfate, filtered and concentrated and theresidue is purified by flash chromatography on silica gel (eluent:dichloromethane). 0.615 g (0.0027 mol) of the title compound (XXg) isrecovered in the form of a yellow oil.

Yield: 84% ¹H NMR (d₆-DMSO) δ: 0.93 (d, 3H), 1.69 (m, 1H), 2.58 (dd,1H), 2.97 (dd, 1H), 3.32 (m, 2H), 3.78 (s, 3H), 4.58 (bs, 1H), 6.77 (m,3H), 8.87 (bs, 1H).

Stage 3: 2-(S)-Methyl-3-(2,3-dimethoxyphenylthio)-propan-1-ol (XXIb)

0.43 g (0.0019 mol) of2-(S)-methyl-3-(2-hydroxy-3-methoxyphenylthio)propan-1-ol (XXg), 10 mlof acetone and 0.26 g (0.0019 mol) of potassium carbonate are introducedinto a round-bottomed flask kept under an inert atmosphere. After 15minutes, 0.12 ml (0.0019 mol) of methyl iodide is introduced and themixture is heated at 60° C. for 8 hours. The mixture is concentratedunder reduced pressure. The residue is taken up in water and the aqueousphase is extracted with dichloromethane. The combined organic phases aredried over magnesium sulfate, filtered and concentrated. The residueobtained is used without additional purification in the following stage.

¹H NMR (d₆-DMSO) δ: 0.95 (d, 3H), 1.75 (m, 1H), 2.62 (dd, 1H), 3.02 (dd,1H), 3.37 (m, 2H), 3.70 (s, 3H), 3.79 (s, 3H), 4.63 (t, 1H), 6.85 (m,2H), 7.04 (m, 1H).

Stage 4: 2-(S)-Methyl-3-(2,3-dimethoxyphenylthio)-propionaldehyde (IIg)

The title compound (IIg) is obtained by carrying out the preparation asin example 7 but by using, in stage 2,2-(S)-methyl-3-(2,3-dimethoxyphenylthio)-propan-1-ol (XXIb) instead of2-(S)-methyl-3-(2-methoxyphenylthio)propan-1-ol (XXb-1). This titlecompound, like the aldehyde (IIb-1), is not isolated but is used in situin the following reductive amination reaction.

Example 163-(R)-([(S)-3,4-Epoxypropyl]amino)-3,4-dihydro-2H-1,5-benzoxathiepine(III-1)

0.85 g (0.0047 mole) of 3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine(Ia-1), 15 ml of 2-propanol and 0.41 ml (0.0052 mol) of(S)-epichlorohydrin are introduced into a round-bottomed flask keptunder an inert atmosphere. The mixture is brought to 60° C. for 12 hoursand then cooled to ambient temperature. 0.37 g (0.0066 mol) of groundpotassium hydroxide is then added and, after stirring at ambienttemperature for 3 hours, the solvent is evaporated under reducedpressure. The residue is taken up in dichloromethane. The solutionobtained is washed with water and with brine, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residueis purified by flash chromatography on silica gel (eluent:dichloromethane/methanol=98:2). 0.69 g (0.0029 mol) of the titlecompound (III-1) is obtained.

Yield: 62% [α]=+22.1 (c=0.227, methanol) ¹H NMR (d₆-DMSO) δ: 2.17 (bs,1H), 2.56 (dd, 1H), 2.65 (m, 2H), 2.84 (m, 2H), 3.00 (m, 1H), 3.11 (m,1H), 3.17 (bs, 1H), 3.93 (dd, 1H), 4.16 (dd, 1H), 6.98 (m, 2H), 7.18(td, 1H), 7.34 (d, 1H) HPLC (Chiralpack AD, hexane/ethanol (90:10), 1ml/min): compound (III-1), retention time=24.04 min; compound (III-2),retention time=29.81 min, ratio of the AUCs (III-1)/(III-2)=97:3

Example 173-(R)-([(R)-3,4-Epoxypropyl]amino)-3,4-dihydro-2H-1,5-benzoxathiepine(III-2)

The title compound (III-2) is obtained, in the form of a white oil, bycarrying out the preparation as in example 16 but by replacing(S)-epichlorohydrin with (R)-epichlorohydrin.

Yield: 55% [α]=+56 (c=0.256, methanol) ¹H NMR (CDCl₃) δ: 2.08 (bs, 1H),2.65 (m, 1H), 2.75 (dd, 1H), 2.80 (m, 1H), 2.97 (dd, 1H), 3.05 (dd, 1H),3.12 (m, 2H), 3.28 (m, 1H), 4.09 (dd, 1H), 4.29 (dd, 1H), 6.96 (m, 2H),7.14 (td, 1H), 7.35 (dd, 1H).

Example 18 2-(S)-Methyl-3-(2-(methoxymethoxy)phenylthio)propionaldehyde(Vb)

Stage 1: 2-(S)-Methyl-3-(2-hydroxyphenylthio)-propan-1-ol (XXh)

The title compound (XXh) is obtained by carrying out the preparation asin example 7 but by replacing, in stage 1, 2-methoxythiophenol with2-hydroxythiophenol.

Yield: 100% ¹H NMR (d₆-DMSO) δ: 0.94 (d, 3H), 1.71 (m, 1H), 2.58 (dd,1H), 2.98 (dd, 1H), 3.34 (m, 2H), 4.59 (bs, 1 exchangeable H), 6.77 (m,2H), 7.00 (m, 1H), 7.18 (m, 1H), 9.68 (bs, 1 exchangeable H).

Stage 2: 2-(S)-Methyl-3-(2-(methoxymethoxy)-phenylthio)propan-1-ol(XXIa)

2.47 g (0.012 mol) of 2-(S)-methyl-3-(2-hydroxyphenylthio)propan-1-ol(XXh), 25 ml of dichloromethane, 12.5 ml (0.024 mol) of an aqueoussodium hydroxide solution (2N), 0.55 ml (0.0012 mol) of Aliquat 336 and0.9 ml (0.012 mol) of chloromethyl methyl ether are introduced into a100 ml round-bottomed flask. The mixture is stirred at ambienttemperature for 24 hours and then the phases are separated. The organicphase is washed successively with an aqueous hydrochloric acid solution(1N), an aqueous sodium hydroxide solution (1N), water and brine andthen dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue is purified by flash chromatography on silica gel(eluent: dichloromethane/acetone=96:4). 1.1 g (0.0045 mol) of the titlecompound (XXIa) are recovered in the form of a white oil.

Yield: 38% ¹H NMR (d₆-DMSO) δ: 0.96 (d, 3H), 1.74 (m, 1H), 2.63 (dd,1H), 3.04 (dd, 1H), 3.36 (t, 2H), 3.40 (s, 3H), 4.62 (t, 1 exchangeableH), 5.23 (s, 2H), 6.98 (td, 1H), 7.05 (dd, 1H), 7.12 (td, 1H), 7.25 (dd,1H).

Stage 3: 2-(S)-Methyl-3-(2-(methoxymethoxy)phenylthio)propionaldehyde(Vb)

The title compound (Vb) is obtained by carrying out the preparation asin example 7 but by using, in stage 2,2-(S)-methyl-3-(2-(methoxymethoxy)phenylthio)propan-1-ol (XXIa) insteadof 2-(S)-methyl-3-(2-methoxyphenylthio)propan-1-ol (XXb-1). This titlecompound, like the aldehyde (IIb-1), is not isolated but is used in situin the following reductive amination reaction.

Example 192-(S)-Methyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Vc)

The title compound (Vc) is obtained by carrying out the preparation asin example 18 but by using, in stage 1, 2-hydroxy-3-methylthiophenol(IVa) instead of 2-hydroxythiophenol. This title compound, like thealdehyde (Vb), is not isolated but is used in situ in the followingreductive amination reaction.

Example 202-(S)-Methyl-3-(2-methoxymethoxy-3-ethylphenylthio)propionaldehyde (Vd)

The title compound (Vd) is obtained by carrying out the preparation asin example 18 but by using, in stage 1, 2-hydroxy-3-ethylthiophenol(IVe) instead of 2-hydroxythiophenol. This title compound, like thealdehyde (Vb), is not isolated but is used in situ in the followingreductive amination reaction.

Example 212-(S)-Ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve)

Stage 1: 2-(S)-Ethyl-3-(2-hydroxy-3-methylphenylthio)propan-1-ol (XXj)

0.78 g (0.0034 mol) of the title compound (XXj), in the form of anorange-colored oil, are obtained by carrying out the preparation as inexample 10 but by replacing, in stage 4, 2-methoxythiophenol with2-hydroxy-3-methylthiophenol (IVa).

Yield: 79% ¹H NMR (d₆-DMSO) δ: 0.84 (t, 3H), 1.40 (m, 2H), 1.51 (m, 1H),2.16 (s, 3H), 2.71 (dd, 1H), 2.86 (dd, 1H), 3.39 (dd, 1H), 3.46 (dd,1H), 4.55 (bs, 1 exchangeable H), 6.73 (t, 1H), 6.96 (d, 1H), 7.10 (d,1H), 8.48 (bs, 1 exchangeable H).

Stage 2:2-(S)-Ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve)

The title compound (Ve) is obtained by carrying out the preparation asin example 18 but by using, in stage 2,2-(S)-ethyl-3-(2-hydroxy-3-methylphenylthio)-propan-1-ol (XXj) insteadof 2-(S)-methyl-3-(2-hydroxyphenylthio)propan-1-ol (XXh). This titlecompound, like the aldehyde (Vb), is not isolated but is used in situ inthe following reductive amination reaction.

Example 222-(S)-Isopropyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde(Vf)

The title compound (Vf) is obtained by carrying out the preparation asin example 21 but by using, in stage 1, 2-(S)-isopropyl-3-hydroxypropylp-toluene-sulfonate (XIXf) instead of 2-(S)-ethyl-3-hydroxypropylp-toluenesulfonate (XIXd-1). This title compound, like the aldehyde(Vb), is not isolated but is used in situ in the following reductiveamination reaction.

Example 232-(S)-Methyl-3-(2-methoxymethoxy-3-methoxyphenylthio)propionaldehyde(Vg)

The title compound (Vg) is obtained by carrying out the preparation asin example 18 but by using, in stage 1, 2-mercapto-6-methoxyphenol (IVg)instead of 2-hydroxythiophenol. This title compound, like the aldehyde(Vb), is not isolated but is used in situ in the following reductiveamination reaction.

Example 242-(S)-Methyl-3-(2-methoxymethoxy-3-(isopropyl)phenylthio)propionaldehyde(Vh)

Stage 1: 2-Hydroxy-3-(isopropyl)thiophenol (IVh)

The title compound (IVh) is obtained, in the form of a yellow oil, bycarrying out the preparation as in example 15 but by using, in stage 1,2-isopropylphenol instead of guaiacol. This title compound is used inthe crude form in the following S-alkylation stage, resulting in theintermediate (XXh).

¹H NMR (d₆-DMSO) δ: 1.14 (d, 6H), 3.27 (m, 1H), 4.64 (bs, 1H), 6.73 (m,1H), 6.96 (m, 1H), 7.10 (m, 1H), 8.54 (bs, 1H).

Stage 2:2-(S)-Methyl-3-(2-methoxymethoxy-3-(isopropyl)phenylthio)propionaldehyde(Vh)

The title compound (Vh) is obtained by carrying out the preparation asin example 18 but by using, in stage 1,2-hydroxy-3-(isopropyl)thiophenol (IVh) instead of 2-hydroxythiophenol.This title compound, like the aldehyde (Vb), is not isolated but is usedin situ in the following reductive amination reaction.

Example 252-(S)-Methyl-3-(2-methoxymethoxy-6-methylphenylthio)propionaldehyde (Vj)

The title compound (Vj) is obtained by carrying out the preparation asin example 18 but by using, in stage 1, 2-hydroxy-6-methylphenol (IVc)instead of 2-hydroxythiophenol. This title compound, like the aldehyde(Vb), is not isolated but is used in situ in the following reductiveamination reaction.

Example 263-(R)-[3-(2-Methoxymethoxy-3-methylphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIa)

The amounts of the amine of formula (I) and of the reducing agent usedin the reductive amination reaction are calculated on the basis of aquantitative oxidation reaction of the alcohol of formula (XXI) to thealdehyde of formula (V). 0.43 g (0.0024 mol) of3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1), in solution in 5ml of dichloromethane, is added to a solution, held at −10° C., of thealdehyde (Ve), 0.0023 mol theoretically, composed of the reaction mediumfrom the reaction of the oxidation of the alcohol (XXIJ) to the aldehyde(Ve). After stirring at −10° C. for 10 minutes, 0.75 g (0.0035 mol) ofsodium triacetoxyborohydride is added and the mixture is stirred at −10°C. for 1 hour 30 and then hydrolyzed using a 10% aqueous sodiumcarbonate solution. The phases are separated and the aqueous phase isextracted with dichloromethane. The combined organic phases are washedwith water and with brine, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue is purified by flashchromatography on silica gel (eluent=cyclohexane/ethyl acetate=70:30).0.42 g (0.0097 mol) of the title compound (VIa) is recovered in the formof an oil.

Yield: 41% ¹H NMR (d₆-DMSO) δ: 0.88 (t, 3H), 1.45 (m, 2H), 1.60 (m, 1H),1.98 (m, 1H), 2.24 (s, 3H), 2.64 (bs, 2H), 2.84 (m, 2H), 3.05 (m, 3H),3.53 (s, 3H), 3.93 (dd, 1H), 4.14 (dd, 1H), 4.99 (s, 2H), 7.00 (m, 4H),7.18 (m, 2H), 7.46 (d, 1H).

Example 273-(R)-[3-(2-Methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb)

The title compound (VIb) is obtained by carrying out the preparation asin example 26 but by using2-(S)-methyl-3-(2-methoxymethoxy-3-methylphenylthio)-propionaldehyde(Vc) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 70% ¹H NMR (d₆-DMSO) δ: 1.00 (d, 3H), 1.76 (m, 1H), 2.02 (bs, 1exchangeable H), 2.24 (s, 3H), 2.60 (m, 2H), 2.70 (dd, 1H), 2.81 (dd,1H), 3.09 (m, 3H), 3.53 (s, 3H), 3.92 (dd, 1H), 4.16 (dd, 1H), 4.99 (s,2H), 7.00 (m, 4H), 7.17 (m, 2H), 7.33 (d, 1H).

Example 283-(R)-[3-(2-Methoxymethoxy-3-methylphenylthio)-2-(S)-(isopropyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIc)

The title compound (VIc) is obtained by carrying out the preparation asin example 26 but by using2-(S)-isopropyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde(Vf) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).This title compound is used without additional purification in thefollowing stage.

Yield: 18%

Example 293-(R)-[3-(2-(Methoxymethoxy)phenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VId)

The title compound (VId) is obtained by carrying out the preparation asin example 26 but by using2-(S)-methyl-3-(2-(methoxymethoxy)phenylthio)propionaldehyde (Vb)instead of2-(S)-ethyl-3-(2-(methoxy-methoxy)-3-methylphenylthio)propionaldehyde(Ve).

Yield: 77% ¹H NMR (d₆-DMSO) δ: 1.01 (d, 3H), 1.77 (m, 1H), 2.02 (bs, 1exchangeable H), 2.60 (m, 2H), 2.70 (dd, 1H), 2.81 (dd, 1H), 3.10 (m,3H), 3.40 (s, 3H), 3.92 (dd, 1H), 4.16 (dd, 1H), 5.23 (s, 2H), 7.10 (m,6H), 7.32 (m, 2H)

Example 303-(R)-[3-(2-Methoxymethoxy-3-ethylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIe)

The title compound (VIe) is obtained by carrying out the preparation asin example 26 but by using2-(S)-methyl-3-(2-methoxymethoxy-3-ethylphenylthio)-propionaldehyde (Vd)instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 23% ¹H NMR (CDCl₃) δ: 1.09 (d, 3H), 1.22 (t, 3H), 1.83 (bs, 1H),1.93 (m, 1H), 2.72 (m, 5H), 2.95 (dd, 1H), 3.09 (m, 3H), 3.64 (s, 3H),5.08 (s, 2H), 4.06 (dd, 1H), 4.25 (dd, 1H), 6.99 (m, 4H), 7.14 (m, 2H),7.35 (dd, 1H).

Example 313-(R)-[3-(2-Methoxymethoxy-3-(isopropyl)-phenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIh)

The title compound (VIh) is obtained by carrying out the preparation asin example 26 but by using2-(S)-methyl-3-(2-methoxymethoxy-3-(isopropyl)phenylthio)propionaldehyde(Vh) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 30% ¹H NMR (CDCl₃) δ: 1.10 (d, 3H), 1.21 (d, 6H), 1.70 (bs, 1H),1.92 (m, 1H), 2.63 (dd, 1H), 2.77 (m, 2H), 2.94 (dd, 1H), 3.10 (m, 3H),3.42 (m, 1H), 3.64 (s, 3H), 4.06 (dd, 1H), 4.24 (dd, 1H), 5.07 (s, 2H),6.96 (m, 2H), 7.11 (m, 4H), 7.35 (d, 1H).

Example 323-(R)-[3-(2-Methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine(VIg)

The title compound (VIg) is obtained by carrying out the preparation asin example 26 but by using2-(S)-methyl-3-(2-methoxymethoxy-3-methylphenylthio)-propionaldehyde(Vc) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve)and 3-(R)-amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine (Ic) insteadof 3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1).

Yield: 52% ¹H NMR (d₆-DMSO) δ: 1.00 (d, 3H), 1.78 (bs, 1H), 2.24 (s,3H), 2.31 (s, 3H), 2.55 (bs, 1H), 2.69 (m, 2H), 2.86 (bs, 1H), 3.10 (m,3H), 3.53 (s, 3H), 3.94 (bs, 1H), 4.18 (bd, 1H), 4.99 (s, 2H), 6.81 (d,1H), 6.92 (d, 1H), 7.03 (m, 3H), 7.18 (m, 1H).

Example 333-(R)-[3-(2-Methoxymethoxy-3-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIi)

The title compound (VIi) is obtained by carrying out the preparation asin example 26 but by using2-(S)-methyl-3-(2-methoxymethoxy-3-methoxyphenylthio)-propionaldehyde(Vg) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 76% ¹H NMR (d₆-DMSO) δ: 1.00 (d, 3H), 1.77 (m, 1H), 2.02 (m, 1H),2.55 (m, 1H), 2.64 (m, 1H), 2.70 (dd, 1H), 2.81 (dd, 1H), 3.09 (m, 3H),3.54 (s, 3H), 3.77 (s, 3H), 3.92 (dd, 1H), 4.16 (dd, 1H), 5.05 (s, 2H),6.96 (m, 5H), 7.17 (m, 1H), 7.33 (d, 1H).

Example 343-(R)-[3-(2-Methoxymethoxy-6-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIj)

The title compound (VIj) is obtained by carrying out the preparation asin example 26 but by using2-(S)-methyl-3-(2-methoxymethoxy-6-methylphenylthio)-propionaldehyde(Vj) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 74% ¹H NMR (d₆-DMSO) δ: 0.96 (d, 3H), 1.56 (m, 1H), 1.88 (bs,1H), 2.45 (s, 3H), 2.59 (m, 3H), 2.75 (dd, 1H), 2.89 (m, 3H), 3.42 (s,3H), 3.86 (dd, 1H), 4.09 (dd, 1H), 5.24 (s, 2H), 6.95 (m, 4H), 7.16 (m,2H), 7.33 (dd, 1H).

Reference Example 13-(R)-[3-(2-Methoxyphenylthio)-2-(S)-methoxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-1)

1.43 g (0.0063 mol) of2-(S)-methoxy-3-(2-methoxyphenylthio)propionaldehyde (IIa-1) and 5 ml of1,2-dichloroethane are introduced into a round-bottomed flask held underan inert atmosphere. 0.60 g (0.0063 mol) of3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1), in solution in 5ml of 1,2-dichloroethane, is added dropwise. The mixture is cooled to 0°C. and then 1 g (0.0047 mol) of sodium triacetoxyborohydride isintroduced. The solution is stirred at ambient temperature for 5 hoursand then hydrolyzed using a 10% aqueous sodium bicarbonate solution. Thephases are separated and the aqueous phase is extracted withdichloromethane. The combined organic phases are washed with brine,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue s purified by flash chromatography on silica gel(eluent: dichloromethane/ethyl acetate=90:10). 0.88 g (0.0022 mol) ofthe compound (1-1) is recovered in the form of a yellow oil.

Yield: 36% ¹H NMR (CDCl₃) δ: 1.96 (bs, 1 exchangeable H), 2.81 (dd, 1H),2.98 (m, 2H), 3.12 (m, 4H), 3.41 (s, 3H), 3.49 (m, 1H), 3.90 (s, 3H),4.16 (m, 2H), 6.86 (d, 1H), 6.94 (m, 3H), 7.12 (t, 1H), 7.20 (t, 1H),7.35 (m, 2H).

0.88 g (0.0022 mol) of the product (1-1) is dissolved in 3 ml ofmethanol and then 0.23 g (0.0020 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.90 g (0.0018 mol) ofthe maleate of the compound (1-1) is obtained in the form of a whitesolid.

M.p. 122° C. [α]=−15.3 (c=0.300, methanol) Analysis C₂₄H₂NO₇S₂:

Calc. %: C 56.79 H 5.76 N 2.76 Found: C 56.42 H 5.81 N 2.96¹H NMR (d₆-DMSO) δ: 3.22 (m, 8H), 3.36 (s, 3H), 3.78 (bs, 1H), 3.84 (s,3H), 4.30 (bd, 1H), 4.46 (bd, 1H), 6.04 (s, 2H), 7.00 (m, 4H), 7.24 (m,2H), 7.38 (m, 2H), 8.90 (bs, 2 exchangeable H) HPLC (Chiracel OD,hexane/isopropanol (90:10), 1 ml/min): compound (1-1), retentiontime=25.40 min; compound (1-2), retention time=21.99 min; ratio of theAUCs (1-1)/(1-2)=95:5.

Reference Example 23-(R)-[3-(2-Methoxyphenylthio)-2-(R)-methoxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-2)

The compound (1-2) is obtained by carrying out the preparation as inreference example 1 but by using2-(R)-methoxy-3-(2-methoxyphenylthio)propionaldehyde (IIa-2) instead of2-(S)-methoxy-3-(2-methoxyphenylthio)propionaldehyde (IIa-1).

Yield: 33% ¹H NMR (CDCl₃) δ: 1.95 (bs, 1 exchangeable H), 3.03 (m, 7H),3.41 (s, 3H), 3.50 (m, 1H), 3.90 (s, 3H), 4.16 (m, 2H), 6.86 (d, 1H),6.93 (m, 3H), 7.12 (td, 1H), 7.21 (td, 1H), 7.34 (m, 2H).

0.79 g (0.002 mol) of the product (1-2) is dissolved in 3 ml of methanoland then 0.21 g (0.0018 mol) of maleic acid, dissolved in 2 ml ofmethanol, is added. The solution obtained is concentrated and then ethylether is added. The precipitate formed is filtered off, washed withethyl ether and dried under vacuum at 50° C. 0.90 g (0.0018 mol) of themaleate of the compound (1-2) is obtained in the form of a white solid.

M.p.: 116° C. [α]=+60.5 (c=0.228, methanol) Analysis C₂₄H₂₉NO₇S₂:

Calc. %: C 56.79 H 5.76 N 2.76 Found: C 56.55 H 5.69 N 2.92¹H NMR (d₆-DMSO) δ: 3.21 (m, 8H), 3.36 (s, 3H), 3.81 (bs, 1H), 3.84 (s,3H), 4.26 (bd, 1H), 4.43 (bd, 1H), 6.04 (s, 2H), 7.03 (m, 4H), 7.24 (m,2H), 7.35 (d, 1H), 7.42 (d, 1H), 8.83 (bs, 2 exchangeable H) HPLC(Chiracel OD, hexane/isopropanol (90:10), 1 ml/min): compound (1-2),retention time=20.75 min; compound (1-1), retention time=25.47 min;ratio of the AUCs (1-2)/(1-1)=86:14.

Reference Example 33-(R)-[3-(2-Hydroxyphenylthio)-2-(S)-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-3)

0.5 g (0.0021 mol) of3-(R)-([(S)-3,4-epoxypropyl]amino)-3,4-dihydro-2H-1,5-benzoxathiepine(III-1) and 15 ml of ethanol are introduced into a round-bottomed flaskkept under an inert atmosphere. 0.22 ml (0.0021 mol) of2-hydroxythiophenol is subsequently added dropwise, followed, afterstirring at ambient temperature for 15 minutes, by 0.45 g (0.0042 mol)of sodium carbonate. The mixture is stirred at ambient temperature for12 hours and then concentrated under reduced pressure. The residue istaken up in dichloromethane and the solution obtained is washed withwater and then dried over sodium sulfate, filtered and concentratedunder vacuum. The residue is purified by flash chromatography on silicagel (eluent: dichloromethane/methanol=96:4). 0.58 g (0.0016 mol) of thecompound (1-3) is recovered in the form of a pale yellow oil.

Yield: 76% ¹H NMR (d₆-DMSO) δ: 2.60 (m, 1H), 2.93 (m, 6H), 3.63 (m, 1H),3.97 (dd, 1H), 4.12 (dd, 1H), 6.78 (m, 2H), 7.00 (m, 3H), 7.17 (td, 1H),7.25 (dd, 1H), 7.33 (dd, 1H).

0.57 g (0.0016 mol) of the product (1-3) is dissolved in 3 ml ofmethanol and then 0.13 g (0.0014 mol) of oxalic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.52 g (0.0011 mol) ofthe oxalate of the compound (1-3) is obtained in the form of a whitesolid.

M.p.: 176–7° C. [α]=−5.2 (c=0.309, methanol) Analysis C₂₀H₂₃NO₇S₂:

Calc. %: C 52.96 H 5.11 N 3.09 Found: C 52.90 H 5.15 N 3.26¹H NMR (d₆-DMSO) δ: 2.97 (m, 3H), 3.22 (m, 3H), 3.72 (bs, 1H), 3.91 (m,1H), 4.35 (m, 2H), 6.79 (td, 1H), 6.85 (dd, 1H), 7.06 (m, 3H), 7.24 (m,2H), 7.40 (dd, 1H). HPLC (Chiralpack AD, hexane/ethanol (50:50), 1ml/min): compound (1-3), retention time=23.08 min; compound (1-4),retention time=19.40 min; ratio of the AUCs (1-3)/(1-4)=99:1.

Reference Example 43-(R)-[3-(2-Hydroxyphenylthio)-2-(R)-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-4)

The compound (1-4) is obtained by carrying out the preparation as inreference example 3 but by using3-(R)-([(R)-3,4-epoxypropyl]amino)-3,4-dihydro-2H-1,5-benzoxathiepine(III-2) instead of3-(R)-([(S)-3,4-epoxypropyl]amino)-3,4-dihydro-2H-1,5-benzoxathiepine(III-1).

Yield: 95% ¹H NMR (d₆-DMSO) δ: 2.68 (m, 2H), 2.89 (m, 3H), 3.10 (m, 2H),3.63 (m, 1H), 3.93 (dd, 1H), 4.12 (dd, 1H), 6.79 (m, 2H), 7.00 (m, 3H),7.17 (td, 1H), 7.25 (dd, 1H), 7.34 (dd, 1H).

0.50 g (0.0014 mol) of the product (1-4) is dissolved in 3 ml ofmethanol and then 0.12 g (0.0013 mol) of oxalic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated. Theprecipitate formed is filtered off, washed with ethyl ether and driedunder vacuum at 50° C. 0.53 g (0.0011 mol) of the oxalate of thecompound (1-4) is obtained in the form of a white solid.

M.p.: 135° C. [α]=+60.48 (c=0.248, methanol) Analysis C₂₀H₂₃NO₇S₂:

Calc. %: C 52.96 H 5.11 N 3.09 Found: C 53.33 H 5.12 N 3.15¹H NMR (d₆-DMSO) δ: 2.96 (m, 3H), 3.23 (m, 3H), 3.68 (bs, 1H), 3.90 (m,1H), 4.46 (m, 2H), 6.79 (t, 1H), 6.85 (d, 1H), 7.05 (m, 3H), 7.25 (m,2H), 7.40 (dd, 1H). HPLC (Chiralpack AD, hexane/ethanol (50:50), 1ml/min): compound (1-4), retention time=18.70 min; compound (1-3),retention time=22.71 min; ratio of the AUCs (1-4)/(1-3)=96:4.

Reference Example 53-(R)-[3-(2-Methoxyphenylthio)-2-(S)-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-5)

The compound (1-5) is obtained by carrying out the preparation as inreference example 3 but by using 2-methoxythiophenol instead of2-hydroxythiophenol.

Yield: 38% ¹H NMR (d₆-DMSO) δ: 2.12 (bs, 1 exchangeable H), 2.64 (m,1H), 2.81 (m, 2H), 2.89 (dd, 1H), 3.06 (m, 3H), 3.65 (m, 1H), 3.81 (s,3H), 3.97 (dd, 1H), 4.13 (dd, 1H), 5.07 (d, 1 exchangeable H), 6.95 (m,4H), 7.16 (m, 2H), 7.31 (m, 2H).

0.20 g (0.0005 mol) of the product (1-5) is dissolved in 3 ml ofmethanol and then 0.06 g (0.0005 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate is filtered off, washed with ethylether and dried under vacuum at 50° C. 0.14 g (0.0003 mol) of themaleate of the compound (1-5) is obtained in the form of a white solid.

M.p.: 133–5° C. [α]=−3.2 (c=0.436, methanol) Analysis C₂₃H₂₇NO₇S₂:

Calc. %: C 55.97 H 5.51 N 2.84 Found: C 55.83 H 5.40 N 2.93¹H NMR (d₆-DMSO) δ: 3.03 (m, 3H), 3.25 (d, 2H), 3.30 (bs, 1H), 3.83 (s,3H), 3.86 (bs, 1H), 3.99 (bs, 1H), 4.32 (bd, 1H), 4.47 (bd, 1H), 5.85(bs, 1H), 6.03 (s, 2H), 7.00 (m, 4H), 7.22 (m, 2H), 7.32 (dd, 1H), 7.41(dd, 1H). HPLC (Chiracel OD, hexane/ethanol (80:20), 1 ml/min): compound(1-5), retention time=20.04 min; compound (1-6), retention time=16.29min; ratio of the AUCs (1-5)/(1-6)=95:5.

Reference Example 63-(R)-[3-(2-Methoxyphenylthio)-2-(R)-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-6)

The compound (1-6) is obtained by carrying out the preparation as inreference example 5 but by using3-(R)-([(R)-3,4-epoxypropyl]amino)-3,4-dihydro-2H-1,5-benzoxathiepine(III-2) instead of3-(R)-([(S)-3,4-epoxypropyl]amino)-3,4-dihydro-2H-1,5-benzoxathiepine(III-1).

Yield: 70% ¹H NMR (d₆-DMSO) δ: 2.13 (bs, 1 exchangeable H), 2.68 (m,2H), 2.88 (m, 2H), 2.99 (dd, 1H), 3.10 (m, 2H), 3.65 (m, 1H), 3.81 (s,3H), 3.93 (dd, 1H), 4.12 (dd, 1H), 5.07 (d, 1 exchangeable H), 6.95 (m,4H), 7.16 (m, 2H), 7.31 (m, 2H).

0.52 g (0.0014 mol) of the product (1-6) is dissolved in 3 ml ofmethanol and then 0.15 g (0.0013 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.59 g (0.0012 mol) ofthe maleate of the compound (1-6) is obtained in the form of a whitesolid.

M.p.: 136–8° C. [α]=+60.3 (c=0.745, methanol) Analysis C₂₃H₂₇NO₇S₂:

Calc. %: C 55.97 H 5.51 N 2.84 Found: C 55.99 H 5.59 N 2.96¹H NMR (d₆-DMSO) δ: 3.03 (m, 3H), 3.26 (d, 2H), 3.30 (bs, 1H), 3.83 (s,3H), 3.86 (bs, 1H), 4.00 (bs, 1H), 4.26 (bd, 1H), 4.44 (bd, 1H), 5.85(bs, 1H), 6.03 (s, 2H), 7.04 (m, 4H), 7.22 (m, 2H), 7.33 (dd, 1H), 7.43(dd, 1H). HPLC (Chiracel OD, hexane/ethanol (80:20), 1 ml/min): compound(1-6), retention time=16.29 min; compound (1-5), retention time=20.04min; ratio of the AUCs (1-6)/(1-5)=97:3.

Reference Example 73-(R)-[3-(2-Methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-7)

The compound (1-7) is obtained by carrying out the preparation as inexample 26 but starting from the reaction mixture comprising2-(S)-methyl-3-(2-methoxy-phenylthio)propionaldehyde (IIb-1) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 58% ¹H NMR (CDCl₃) δ: 1.10 (d, 3H), 1.68 (bs, 1 exchangeable H),1.91 (m, 1H), 2.63 (dd, 1H), 2.78 (m, 2H), 2.93 (dd, 1H), 3.10 (m, 3H),3.90 (s, 3H), 4.07 (dd, 1H), 4.23 (dd, 1H), 6.84 (d, 1H), 6.91 (m, 3H),7.14 (m, 2H), 7.33 (m, 2H).

2.85 g (0.0076 mol) of the product (1-7) are dissolved in 5 ml ofmethanol and then 0.84 g (0.0072 mol) of fumaric acid, dissolved in 3 mlof methanol, is added. The solution obtained is concentrated and thenisopropyl ether is added. The precipitate formed is filtered off, washedwith isopropyl ether and dried under vacuum at 50° C. 3.36 g (0.0068mol) of the fumarate of the compound (1-7) are obtained in the form of awhite solid.

M.p.: 133–4° C. [α]=−1.2 (c=0.446, methanol) Analysis C₂₄H₂₉NO₆S₂:

Calc. %: C 58.63 H 5.95 N 2.85 Found: C 58.53 H 5.89 N 2.74¹H NMR (d₆-DMSO) δ: 1.01 (d, 3H), 1.80 (m, 1H), 2.59 (dd, 1H), 2.69 (m,2H), 2.87 (dd, 1H), 3.11 (m, 3H), 3.81 (s, 3H), 3.98 (dd, 1H), 4.19 (dd,1H), 6.61 (s, 2H), 6.96 (m, 4H), 7.16 (m, 2H), 7.27 (d, 1H), 7.34 (d,1H). HPLC (Chiracel OD, hexane/isopropanol (80:20), 1 ml/min): compound(1-7), retention time=13.09 min; compound (1-8), retention time=9.15min; ratio of the AUCs (1-7)/(1-8)=99:1.

Reference Example 83-(R)-[3-(2-Methoxyphenylthio)-2-(R)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-8)

The compound (1-8) is obtained by carrying out the preparation as inexample 26 but starting from the reaction mixture comprising2-(R)-methyl-3-(2-methoxy-phenylthio)propionaldehyde (IIb-2) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 58% ¹H NMR (CDCl₃) δ: 1.10 (d, 3H), 1.68 (bs, 1 exchangeable H),1.91 (m, 1H), 2.63 (dd, 1H), 2.78 (m, 2H), 2.93 (dd, 1H), 3.10 (m, 3H),3.90 (s, 3H), 4.07 (dd, 1H), 4.23 (dd, 1H), 6.84 (d, 1H), 6.91 (m, 3H),7.14 (m, 2H), 7.33 (m, 2H).

0.60 g (0.0016 mol) of the product (1-8) is dissolved in 3 ml ofmethanol and then 0.18 g (0.0015 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.72 g (0.0014 mol) ofthe maleate of the compound (1-8) is obtained in the form of a whitesolid.

M.p.: 140° C. [α]=+52.4 (c=0.254, methanol) Analysis C₂₄H₂₉NO₆S₂:

Calc. %: C 58.63 H 5.95 N 2.85 Found: C 58.48 H 5.99 N 3.13¹H NMR (d₆-DMSO) δ: 1.11 (d, 3H), 2.13 (m, 1H), 2.83 (dd, 1H), 2.98 (m,1H), 3.06 (dd, 1H), 3.24 (m, 4H), 3.82 (s, 3H), 4.33 (bd, 1H), 4.44 (bd,1H), 6.03 (s, 2H), 7.02 (m, 4H), 7.24 (m, 3H), 7.40 (d, 1H). HPLC(Chiralpack AS, methanol, 1 ml/min): compound (1-7), retentiontime=10.67 min; compound (1-8), retention time=8.81 min; ratio of theAUCs (1-8)/(1-7)=87:13.

Reference Example 93-(R)-[3-(2-Methoxyphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-9)

The compound (1-9) is obtained by carrying out the preparation as inexample 26 but starting from the reaction mixture comprising2-(S)-ethyl-3-(2-methoxyphenylthio)propionaldehyde (IId-1) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 93% ¹H NMR (d₆-DMSO) δ: 0.87 (t, 3H), 1.44 (m, 2H), 1.59 (m, 1H),1.98 (bs, 1H), 2.64 (m, 2H), 2.82 (m, 2H), 3.04 (m, 3H), 3.80 (s, 3H),3.93 (dd, 1H), 4.14 (dd, 1H), 6.96 (m, 4H), 7.15 (m, 2H), 7.28 (dd, 1H),7.33 (dd, 1H).

1.1 g (0.0028 mol) of the product (1-9) are dissolved in 5 ml ofmethanol and then 0.29 g (0.0025 mol) of fumaric acid, dissolved in 3 mlof methanol, is added. The solution obtained is concentrated and thenpentane is added. The precipitate formed is filtered off, washed withpentane and dried under vacuum at 50° C. 1.19 g (0.0023 mol) of thefumarate of the compound (1-9) are obtained in the form of a whitesolid.

M.p.: 86–8° C. [α]=−8 (c=0.512, methanol) Analysis C₂₅H₃₁NO₆S₂:

Calc. %: C 59.38 H 6.18 N 2.77 Found: C 59.32 H 6.18 N 2.98¹H NMR (d₆-DMSO) δ: 0.87 (t, 3H), 1.44 (m, 2H), 1.63 (m, 1H), 2.68 (m,2H), 2.85 (m, 2H), 3.02 (dd, 1H), 3.11 (m, 2H), 3.80 (s, 3H), 3.97 (dd,1H), 4.16 (dd, 1H), 6.61 (s, 2H), 6.96 (m, 4H), 7.16 (m, 2H), 7.29 (dd,1H), 7.34 (m, 1H). HPLC (Chiracel OD, hexane/isopropanol (95:5), 1ml/min): compound (1-9), retention time=16.62 min; compound (1-10),retention time=14.69 min; ratio of the AUCs (1-9)/(1-10)=97:3.

Reference Example 103-(R)-[3-(2-Methoxyphenylthio)-2-(R)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-10)

The compound (1-10) is obtained by carrying out the preparation as inexample 26 but starting from the reaction mixture comprising2-(R)-ethyl-3-(2-methoxyphenylthio)propionaldehyde (IId-2) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 49% ¹H NMR (d₆-DMSO) δ: 0.86 (t, 3H), 1.43 (m, 2H), 1.56 (m, 1H),2.89 (m, 7H), 3.80 (s, 3H), 3.91 (dd, 1H), 4.14 (dd, 1H), 6.95 (m, 4H),7.24 (m, 4H).

0.17 g (0.0044 mol) of the product (1-10) is dissolved in 3 ml ofmethanol and then 0.05 g (0.0043 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.15 g (0.0030 mol) ofthe maleate of the compound (1-10) is obtained in the form of a whitesolid.

M.p.: 140° C. [α]=+71.7 (c=0.318, methanol) Analysis C₂₅H₃₁NO₆S₂:

Calc. %: C 59.38 H 6.18 N 2.77 Found: C 59.20 H 6.07 N 2.93¹H NMR (d₆-DMSO) δ: 0.90 (t, 3H), 1.52 (m, 2H), 1.99 (m, 1H), 3.16 (m,7H), 3.82 (s, 3H), 4.33 (bd, 1H), 4.44 (m, 1H), 6.04 (s, 2H), 7.02 (m,4H), 7.24 (m, 3H), 7.40 (d, 1H). HPLC (Chiracel OD, hexane/isopropanol(95:5), 1 ml/min): compound (1-10), retention time=14.01 min; compound(1-9), retention time=16.47 min; ratio of the AUCs (1-10)/(1-9)=98:2.

Reference Example 113-(R)-[3-(2-Methoxyphenylthio)-2-(S)-(n-propyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-11)

The compound (1-11) is obtained by carrying out the preparation as inexample 26 but starting from the reaction mixture comprising2-(S)-(n-propyl)-3-(2-methoxyphenylthio)propionaldehyde (IIe-1) insteadof 2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)-propionaldehyde(Ve).

Yield: 80% ¹H NMR (d₆-DMSO) δ: 0.85 (t, 3H), 1.33 (m, 4H), 1.65 (m, 1H),1.96 (m, 1H), 2.63 (m, 2H), 2.82 (m, 2H), 3.03 (m, 3H), 3.80 (s, 3H),3.92 (dd, 1H), 4.14 (dd, 1H), 6.95 (m, 4H), 7.16 (m, 2H), 7.28 (d, 1H),7.34 (d, 1H).

0.31 g (0.0077 mol) of the product (1-11) is dissolved in 3 ml ofmethanol and then 0.08 g (0.0070 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.31 g (0.0060 mol) ofthe maleate of the compound (1-11) is obtained in the form of a whitesolid.

M.p.: 132–3° C. [α]=−12.7 (c=0.434, methanol) Analysis C₂₆H₃₃NO₆S₂:

Calc. %: C 60.09 H 6.40 N 2.70 Found: C 60.13 H 6.29 N 2.87¹H NMR (d₆-DMSO) δ: 0.87 (t, 3H), 1.32 (m, 2H), 1.45 (m, 2H), 2.05 (bs,1H), 3.13 (m, 8H), 3.82 (s, 3H), 4.33 (bd, 1H), 4.43 (bd, 1H), 6.04 (s,2H), 7.02 (m, 4H), 7.24 (m, 3H), 7.40 (d, 1H). HPLC (Chiralpack AD,hexane/ethanol (97:3), 1 ml/min): compound (1-11), retention time=8.65min; compound (1-12), retention time=9.16 min; ratio of the AUCs(1-11)/(1-12)=93:7.

Reference Example 123-(R)-[3-(2-Methoxyphenylthio)-2-(R)-(n-propyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-12)

The compound (1-12) is obtained by carrying out the preparation as inexample 26 but starting from the reaction mixture comprising2-(R)-(n-propyl)-3-(2-methoxyphenylthio)propionaldehyde (IIe-2) insteadof 2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)-propionaldehyde(Ve).

Yield: 47% ¹H NMR (CDCl₃) δ: 0.90 (t, 3H), 1.37 (m, 2H), 1.46 (m, 2H),1.81 (m, 1H), 2.74 (m, 2H), 3.03 (m, 5H), 3.90 (s, 3H), 4.08 (dd, 1H),4.20 (dd, 1H), 6.84 (d, 1H), 6.94 (m, 3H), 7.14 (m, 2H), 7.34 (m, 2H).

0.16 g (0.0039 mol) of the product (1-12) is dissolved in 3 ml ofmethanol and then 0.04 g (0.0034 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.12 g (0.0023 mol) ofthe maleate of the compound (1-12) is obtained in the form of a whitesolid.

M.p.: 131–3° C. [α]=+63.3 (c=0.216, methanol) Analysis C₂₆H₃₃NO₆S₂:

Calc. %: C 60.09 H 6.40 N 2.70 Found: C 60.15 H 6.56 N 2.79¹H NMR (d₆-DMSO) δ: 0.87 (t, 3H), 1.32 (m, 2H), 1.46 (m, 2H), 2.05 (bs,1H), 3.16 (m, 8H), 3.82 (s, 3H), 4.33 (bd, 1H), 4.43 (bs, 1H), 6.04 (s,2H), 7.02 (m, 4H), 7.24 (m, 3H), 7.40 (d, 1H). HPLC (Chiralpack AD,hexane/ethanol (97:3), 1 ml/min): compound (1-12), retention time=9.15min; compound (1-11), retention time=8.66 min; ratio of the AUCs(1-12)/(1-11)=94:6.

Reference Example 133-(R)-[3-(2-Methoxyphenylthio)-2-(S)-(isopropyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-13)

The compound (1-13) is obtained by carrying out the preparation as inexample 26 but starting with the reaction mixture comprising2-(S)-isopropyl-3-(2-methoxyphenylthio)propionaldehyde (IIf) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)-propionaldehyde(Ve).

Yield: 70% ¹H NMR (d₆-DMSO) δ: 0.88 (d, 3H), 0.90 (d, 3H), 1.46 (m, 1H),1.92 (m, 2H), 2.65 (m, 2H), 2.82 (dd, 1H), 2.91 (m, 2H), 3.08 (m, 2H),3.80 (s, 3H), 3.94 (dd, 1H), 4.13 (dd, 1H), 6.95 (m, 4H), 7.15 (m, 2H),7.32 (m, 2H).

0.31 g (0.0077 mol) of the product (1-13) is dissolved in 3 ml ofmethanol and then 0.08 g (0.0069 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered, washed withethyl ether and dried under vacuum at 50° C. 0.32 g (0.0061 mol) of themaleate of the compound (1-13) is obtained in the form of a white solid.

M.p.: 114–5° C. [α]=−29.6 (c=0.361, methanol) Analysis C₂₆H₃₃NO₆S₂:

Calc. %: C 60.09 H 6.40 N 2.70 Found: C 60.03 H 6.61 N 2.83¹H NMR (d₆-DMSO) δ: 0.89 (d, 3H), 0.93 (d, 3H), 1.90 (bs, 1H), 2.02 (m,1H), 2.94 (dd, 1H), 3.06 (m, 3H), 3.30 (m, 3H), 3.81 (s, 3H), 4.32 (bd,1H), 4.44 (bs, 1H), 6.04 (s, 3H), 6.97 (m, 2H), 7.08 (m, 2H); 7.22 (m,2H), 7.31 (dd, 1H), 7.41 (dd, 1H).

Reference Example 143-(R)-[3-(2-Methoxyphenylthio)-2-(S)-methylpropyl]amino-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine(1-14)

The compound (1-14) is obtained, in the form of a colorless oil, bycarrying out the preparation as in example 26 but starting from thereaction mixture comprising2-(S)-methyl-3-(2-methoxyphenylthio)propionaldehyde (IIb-1) instead of2-(S)-ethyl-3-(2-methoxy-methoxy-3-methylphenylthio)propionaldehyde (Ve)and by using 3-(R)-amino-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine(Ib) instead of 3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1).

Yield: 36% ¹H NMR (CDCl₃) δ: 1.10 (d, 3H), 1.68 (bs, 1H), 1.91 (m, 1H),2.25 (s, 3H), 2.62 (dd, 1H), 2.77 (m, 2H), 2.92 (dd, 1H), 3.08 (m, 3H),3.90 (s, 3H), 4.00 (dd, 1H), 4.20 (dd, 1H), 6.88 (m, 4H), 7.15 (m, 2H),7.31 (dd, 1H).

0.22 g (0.0056 mol) of the product (1-14) is dissolved in 3 ml ofmethanol and then 0.065 g (0.0056 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and a whiteprecipitate is formed; it is filtered off and dried under vacuum at 50°C. 0.25 g (0.0049 mol) of the maleate of the compound (1-14) is obtainedin the form of a white solid.

M.p.: 148° C. [α]=12.2 (c=0.302, methanol) Analysis C₂₅H₃₁NO₆S₂:

Calc. %: C 59.38 H 6.18 N 2.77 Found: C 59.63 H 6.20 N 2.95¹H NMR (d₆-DMSO) δ: 1.10 (d, 3H), 2.13 (m, 1H), 2.23 (s, 3H), 2.81 (dd,1H), 2.97 (m, 1H), 3.09 (dd, 1H), 3.25 (m, 4H), 3.78 (bs, 1H), 3.82 (s,3H), 4.24 (bd, 1H), 4.41 (bd, 1H), 6.04 (s, 2H), 6.99 (m, 4H), 7.19 (m,2H), 7.28 (d, 1H).

Reference Example 153-(R)-[3-(2-Methoxyphenylthio)-2-(S)-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine(1-15)

The compound (1-15) is obtained, in the form of a colorless oil, bycarrying out the preparation as in example 26 but starting from thereaction mixture comprising2-(S)-methyl-3-(2-methoxyphenylthio)propionaldehyde (IIb-1) instead of2-(S)-ethyl-3-(2-methoxy-methoxy-3-methylphenylthio)propionaldehyde (Ve)and by using 3-(R)-amino-6-methyl-3,4-dihydro-2H,1,5-benzoxathiepine(Ic) instead of 3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1).

Yield: 23% ¹H NMR (d₆-DMSO) δ: 1.00 (d, 3H), 1.75 (m, 1H), 1.99 (bs,1H), 2.31 (s, 3H), 2.53 (m, 1H), 2.66 (m, 2H), 2.84 (dd, 1H), 3.09 (m,3H), 3.80 (s, 3H), 3.92 (dd, 1H), 4.17 (bd, 1H), 6.81 (d, 1H), 6.94 (m,3H), 7.02 (t, 1H), 7.15 (td, 1H), 7.27 (d, 1H).

0.10 g (0.0026 mol) of the product (1-15) is dissolved in 3 ml ofmethanol and then 0.03 g (0.0026 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.11 g (0.0022 mol) ofthe maleate of the compound (1-15) is obtained in the form of a whitesolid.

M.p.: 111–3° C. [α]=+16.3 (c=0.214, methanol) Analysis C₂₅H₃₁NO₆S₂:

Calc. %: C 59.38 H 6.18 N 2.77 Found: C 58.74 H 6.20 N 3.01¹H NMR (d₆-DMSO) δ: 1.10 (d, 3H), 2.12 (bs, 1H), 2.33 (s, 3H), 2.81 (dd,1H), 2.99 (bs, 1H), 3.09 (dd, 1H), 3.28 (bm, 5H), 3.82 (s, 3H), 4.39(bm, 2H), 6.04 (s, 2H), 6.90 (d, 1H), 6.97 (m, 3H), 7.10 (t, 1H), 7.20(td, 1H), 7.28 (dd, 1H).

Reference Example 163-(R)-[3-(2,3-Dihydrobenzofuran-7-thio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-16)

The compound (1-16) is obtained, in the form of a colorless oil, bycarrying out the preparation as in example 26 but starting from thereaction mixture comprising2-(S)-methyl-3-(2,3-dihydrobenzofuran-7-thio)propionaldehyde (IIc)instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)propionaldehyde (Ve).

Yield: 40% ¹H NMR (d₆-DMSO) δ: 0.96 (d, 3H), 1.70 (m, 1H), 1.97 (bs,1H), 2.67 (m, 4H), 3.07 (m, 3H), 3.19 (t, 2H), 3.32 (s, 3H), 3.89 (dd,1H), 4.14 (bd, 1H), 4.54 (t, 2H), 6.79 (t, 1H), 6.97 (m, 2H), 7.08 (m,2H), 7.17 (m, 1H), 7.33 (d, 1H).

0.20 g (0.0005 mol) of the product (1-16) is dissolved in 3 ml ofmethanol and 0.055 g (0.0005 mol) of maleic acid dissolved in 2 ml ofmethanol, is added. The solution obtained is concentrated and then ethylether is added. The precipitate formed is filtered off, washed withethyl ether and dried under vacuum at 50° C. 0.15 g (0.0003 mol) of themaleate of the compound (1-16) is obtained in the form of a white solid.

M.p.: 116–8° C. [α]=+8.2 (c=0.291, methanol) Analysis C₂₅H₂₉NO₆S₂:

Calc. %: C 59.62 H 5.80 N 2.78 Found: C 59.51 H 5.70 N 3.06¹H NMR (d₆-DMSO) δ: 1.07 (d, 3H), 2.06 (bs, 1H), 2.83 (m, 1H), 2.95 (bs,1H), 3.08 (m, 2H), 3.21 (t, 2H), 3.25 (m, 2H), 3.79 (bs, 1H), 4.33 (bd,1H), 4.42 (bs, 1H), 4.56 (t, 2H), 6.04 (s, 2H), 6.82 (t, 1H), 7.09 (m,4H), 7.24 (td, 1H), 7.40 (d, 1H).

Reference Example 173-(R)-[3-(2-Hydroxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-17)

0.69 g (0.0016 mol) of3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb), 10 ml of methanol and 3 ml of hydrochloric acid (5N) areintroduced into a 100 ml round bottomed flask. The mixture is brought to50° C. for 12 hours. The methanol is evaporated under reduced pressure,then 3 ml of an aqueous sodium hydroxide solution (5N) are added and themixture is extracted with dichloromethane. The combined organic phasesare dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue is purified by flash chromatography on silica gel(eluent: dichloromethane/methanol=99:1). 0.31 g (0.0008 mol) of thecompound (1-17) is recovered in the form of a colorless oil.

Yield: 37% ¹H NMR (d₆-DMSO) δ: 0.98 (d, 3H), 1.73 (m, 1H), 2.16 (s, 3H),2.61 (m, 3H), 2.81 (dd, 1H), 2.96 (dd, 1H), 3.07 (m, 2H), 3.92 (dd, 1H),4.15 (dd, 1H), 6.72 (t, 1H), 6.98 (m, 3H), 7.16 (m, 2H), 7.34 (d, 1H).0.31 g (0.0008 mol) of the product (1-17) is dissolved in 3 ml ofmethanol and then 0.09 g (0.0008 mol) of maleic acid, dissolved in 2 mlof methanols is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.25 g (0.0005 mol) ofthe maleate of the compound (1-17) is obtained in the form of a whitesolid.

M.p.: 124–6° C. [α]=−1.2 (c=0.255, methanol) Analysis C₂₄H₂₉NO₆S₂:

Calc. %: C 59.63 H 5.94 N 2.85 Found: C 59.23 H 5.78 N 2.80¹H NMR (d₆-DMSO) δ: 1.09 (d, 3H), 2.07 (bs, 1H), 2.17 (s, 3H), 2.75 (dd,1H), 2.98 (m, 2H), 3.16 (bs, 1H), 3.26 (m, 2H), 3.80 (bs, 1H), 4.35 (bd,1H), 4.45 (bd, 1H), 6.04 (s, 2H), 6.76 (t, 1H), 7.00 (d, 1H), 7.06 (m,2H), 7.16 (d, 1H), 7.25 (td, 1H), 7.39 (dd, 1H).

Reference Example 183-(R)-[3-(2-Hydroxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-18)

The compound (1-18) is obtained, in the form of a pale yellow oil, bycarrying out the preparation as in reference example 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-(methoxymethoxy)phenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VId)

Yield: 95% ¹H NMR (d₆-DMSO) δ: 0.99 (d, 3H), 1.73 (m, 1H), 2.59 (m, 3H),2.80 (m, 1H), 3.05 (m, 3H), 3.91 (dd, 1H), 4.15 (bd, 1H), 6.78 (m, 2H),6.99 (m, 3H), 7.19 (m, 2H), 7.33 (m, 1H).

1.2 g (0.0033 mol) of the product (1-18) are dissolved in 5 ml ofmethanol and then 0.3 g (0.0026 mol) of maleic acid, dissolved in 3 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.88 g (0.0018 mol) ofthe maleate of the compound (1-18) is obtained in the form of a whitesolid.

M.p.: 119–21° C. [α]=15.3 (c=0.416, methanol) Analysis C₂₃H₂₇NO₆S₂:

Calc. %: C 57.84 H 5.70 N 2.93 Found: C 57.51 H 5.82 N 2.80¹H NMR (d₆-DMSO) δ: 1.09 (d, 3H), 2.1 (m, 1H), 2.79 (dd, 1H), 2.95 (m,1H), 3.05 (dd, 1H), 3.18 (m, 1H), 3.29 (m, 3H), 3.81 (bs, 1H), 4.35 (bd,1H), 4.45 (bd, 1H), 6.04 (s, 2H), 6.82 (m, 2H), 7.06 (m, 3H), 7.24 (m,2H), 7.39 (dd, 1H).

Reference Example 193-(R)-[3-(2-Hydroxy-3-ethylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-19)

The compound (1-19) is obtained, in the form of a colorless oil, bycarrying out the preparation as in reference example 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-methoxymethoxy-3-ethylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIe).

Yield: 33% ¹H NMR (CDCl₃) δ: 1.04 (d, 3H), 1.22 (t, 3H), 1.91 (m, 1H),2.67 (q, 2H), 2.79 (m, 4H), 3.05 (m, 2H), 3.15 (m, 1H), 4.02 (dd, 1H),4.34 (dd, 1H), 6.77 (t, 1H), 6.98 (m, 2H), 7.13 (m, 2H), 7.32 (dd, 1H),7.37 (dd, 1H).

0.11 g (0.0003 mol) of the product (1-19) is dissolved in 3 ml ofmethanol and then 0.033 g (0.00028 mol) of maleic acid, dissolved in 2ml of methanol, is added. The solution obtained is concentrated andethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.075 g (0.00015 mol)of the maleate of the compound (1-19) is obtained in the form of a whitesolid.

M.p.: 120° C. [α]=+1.4 (c=0.280, methanol) Analysis C₂₅H₃₁NO₆S₂:

Calc. %: C 59.38 H 6.18 N 2.77 Found: C 59.18 H 6.28 N 2.68¹H NMR (d₆-DMSO) δ: 1.11 (m, 6H); 2.07 (bs, 1H), 2.58 (q, 2H), 2.74 (dd,1H), 2.99 (m, 2H), 3.21 (m, 3H), 3.79 (bs, 1H), 4.34 (bd, 1H), 4.42 (bs,1H), 6.04 (s, 2H), 6.80 (t, 1H), 7.05 (m, 3H), 7.17 (d, 1H), 7.24 (td,1H), 7.39 (d, 1H), 8.56 (bs, 1 exchangeable H).

Reference Example 203-(R)-[3-(2-Hydroxy-3-methylphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-20)

The compound (1-20) is obtained, in the form of a colorless oil, bycarrying out the preparation as in reference example 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIa).

Yield: 91% ¹H NMR (d₆-DMSO) δ: 0.85 (t, 3H), 1.42 (m, 2H), 1.57 (m, 1H),2.16 (s, 3H), 2.66 (m, 2H), 2.85 (m, 3H), 3.07 (m, 2H), 3.94 (dd, 1H),4.14 (dd, 1H), 6.72 (t, 1H), 6.98 (m, 3H), 7.17 (m, 2H), 7.34 (d, 1H)

0.32 g (0.0008 mol) of the product (1-20) is dissolved in 3 ml ofmethanol and then 0.09 g (0.0008 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.31 g (0.0006 mol) ofthe maleate of the compound (1-20) is obtained in the form of a whitesolid.

M.p.: 111–2° C. [α]=−7.8 (c=0.332, methanol) Analysis C₂₅H₃₁NO₆S₂:

Calc. %: C 59.38 H 6.18 N 2.77 Found: C 59.04 H 6.28 N 2.84¹H NMR (d₆-DMSO) δ: 0.87 (t, 3H), 1.52 (m, 2H), 1.94 (bs, 1H), 2.17 (s,3H), 3.07 (m, 6H), 3.81 (bs, 1H), 4.34 (bd, 1H), 4.43 (bd, 1H), 6.04 (s,2H), 6.76 (t, 1H), 7.00 (d, 1H), 7.06 (m, 2H), 7.16 (d, 1H), 7.25 (td,1H), 7.40 (d, 1H), 8.64 (bs, exchangeable H).

Reference Example 213-(R)-[3-(2-Hydroxy-3-methylphenylthio)-2-(S)-(isopropyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-21)

The compound (1-21), which is not purified at this stage but salifieddirectly, is obtained by carrying out the preparation as in referenceexample 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-(isopropyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIc).

Crude yield: 84%

0.083 g (0.0002 mol) of the product (1-21) is dissolved in 3 ml ofmethanol and then 0.024 g (0.0002 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.08 g (0.00015 mol)of the maleate of the compound (1-21) is obtained in the form of a whitesolid.

M.p.: 127° C. [α]=−29.4 (c=0.211, methanol) Analysis C₂₆H₃₃NO₆S₂:

Calc. %: 60.09 H 6.40 N 2.70 Found: C 59.85 H 6.43 N 2.77¹H NMR (d₆-DMSO) δ: 0.85 (d, 3H), 0.90 (d, 3H), 1.85 (bs, 1H), 2.01 (bs,1H), 2.17 (s, 3H), 2.86 (dd, 1H), 2.96 (dd, 1H), 3.10 (bs, 1H), 3.29(bs, 3H), 3.83 (bs, 1H), 4.34 (d, 1H), 4.44 (bs, 1H), 6.04 (s, 2H), 6.76(t, 1H), 7.00 (d, 1H), 7.07 (m, 2H), 7.17 (d, 1H), 7.25 (t, 1H), 7.40(d, 1H), 8.65 (bs, exchangeable H).

Reference Example 223-(R)-[3-(2-Hydroxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine(1-22)

The compound (1-22) is obtained, in the form of a colorless oil, bycarrying out the preparation as in reference example 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine(VIg).

Yield: 95% ¹H NMR (d₆-DMSO) δ: 0.98 (d, 3H), 1.74 (m, 1H), 2.16 (s, 3H),2.31 (s, 3H), 2.55 (m, 1H), 2.41 (m, 2H), 2.86 (m, 1H), 2.96 (dd, 1H),3.11 (m, 2H), 3.94 (bs, 1H), 4.17 (bd, 1H), 6.72 (t, 1H), 6.81 (d, 1H),6.92 (d, 1H), 6.97 (d, 1H), 7.03 (t, 1H), 7.14 (d, 1H).

0.315 g (0.0008 mol) of the product (1-22) is dissolved in 3 ml ofmethanol and then 0.084 g (0.0007 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.35 g (0.0007 mol) ofthe maleate of the compound (1-22) is obtained in the form of a whitesolid.

M.p.: 108–9° C. [α]=+13.4 (c=0.209, methanol) Analysis C₂₅H₃₁NO₆S₂:

Calc. %: C 59.38 H 6.18 N 2.77 Found: C 59.38 H 6.26 N 3.00¹H NMR (d₆-DMSO) δ: 1.09 (d, 3H), 2.06 (m, 1H), 2.17 (s, 3H), 2.33 (s,3H), 2.75 (dd, 1H), 2.99 (m, 2H), 3.16 (bs, 1H), 3.27 (m, 3H), 3.79 (bs,1H), 4.39 (m, 2H), 6.04 (s, 2H), 6.76 (t, 1H), 6.90 (d, 1H), 7.00 (m,2H), 7.10 (t, 1H), 7.16 (d, 1H).

Reference Example 233-(R)-[3-(2-Hydroxy-3-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-23)

The compound (1-23), which is not purified at this stage but salifieddirectly, is obtained by carrying out the preparation as in referenceexample 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-methoxymethoxy-3-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIi).

Crude yield: 73%

0.13 g (0.0003 mol) of the product (1-23) is dissolved in 3 ml ofmethanol and then 0.035 g (0.0003 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.103 g (0.0002 mol)of the maleate of the compound (1-23) is obtained in the form of a whitesolid.

M.p.: 137–9° C. [α]=−11.6 (c=0.268, methanol) Analysis C₂₄H₂₉NO₇S₂:

Calc. %: C 56.78 H 5.76 N 2.76 Found: C 56.82 H 5.85 N 2.89¹H NMR (d₆-DMSO) δ: 1.08 (d, 3H), 2.07 (m, 1H), 2.79 (dd, 1H), 2.96 (m,1H), 3.04 (dd, 1H), 3.17 (m, 1H), 3.27 (m, 3H), 3.79 (s, 3H), 4.35 (bd,1H), 4.44 (bd, 1H), 6.04 (s, 2H), 6.77 (m, 1H), 6.86 (m, 2H), 7.06 (m,2H), 7.24 (m, 1H), 7.39 (d, 1H), 8.79 (bs, exchangeable), 9.02 (bs,exchangeable).

Reference Example 243-(R)-[3-(2,3-Dimethoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-24)

The compound (1-24) is obtained by carrying out the preparation as inexample 26 but starting from the reaction mixture comprising2-(S)-methyl-3-(2,3-dimethoxyphenylthio)propionaldehyde (IIg) instead of2-(S)-ethyl-3-(2-methoxymethoxy-3-methylphenylthio)-propionaldehyde(Ve).

Yield: 37% ¹H NMR (CDCl₃) δ: 1.00 (d, 3H), 1.78 (m, 1H), 2.02 (bs, 1H),2.62 (m, 3H), 2.81 (dd, 1H), 3.08 (m, 3H), 3.70 (s, 3H), 3.78 (s, 3H),3.92 (dd, 1H), 4.17 (dd, 1H), 6.86 (m, 2H), 7.01 (m, 3H), 7.17 (m, 1H),7.33 (d, 1H).

0.22 g (0.0005 mol) of the product (1-24) is dissolved in 3 ml ofmethanol and then 0.057 g (0.0005 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.175 g (0.0003 mol)of the maleate of the compound (1-24) is obtained in the form of a whitesolid.

M.p.: 117–9° C. [α]=+1 (c=0.270, methanol) Analysis C₂₅H₃₁NO₇S₂:

Calc. %: C 57.56 H 5.99 N 2.68 Found: C 57.16 H 5.82 N 2.92¹H NMR (d₆-DMSO) δ: 1.11 (d, 3H), 2.14 (bs, 1H), 2.82 (dd, 1H), 2.98(bs, 1H), 3.11 (dd, 1H), 3.17 (bs, 1H), 3.30 (m, 3H), 3.72 (s, 3H), 3.79(s, 3H), 4.34 (bd, 1H), 4.40 (bs, 1H), 6.89 (m, 2H), 7.06 (m, 3H), 7.25(m, 1H), 7.40 (dd, 1H), 8.78 (bs, exchangeable H).

Reference Example 253-(R)-[3-(2-Hydroxy-3-(isopropyl)phenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-25)

The compound (1-25) is obtained, in the form of a colorless oil, bycarrying out the preparation as in reference example 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-methoxymethoxy-3-(isopropyl)phenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIh).

Yield: 68% ¹H NMR (CDCl₃) δ: 1.05 (d, 3H), 1.23 (d, 6H), 1.55 (bs,exchangeable H), 1.91 (m, 1H), 2.76 (m, 3H), 2.86 (dd, 1H), 3.04 (m,2H), 3.14 (bs, 1H), 3.32 (m, 1H), 4.02 (dd, 1H), 4.33 (dd, 1H), 6.80 (m,1H), 6.97 (m, 2H), 7.15 (m, 2H), 7.34 (m, 2H).

0.124 g (0.0003 mol) of the product (1-25) is dissolved in 3 ml ofmethanol and then 0.036 g (0.0003 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered off, washedwith ethyl ether and dried under vacuum at 50° C. 0.155 g (0.0003 mol)of the maleate of the compound (1-25) is obtained in the form of a whitesolid.

M.p.: 126° C. [α]=+4.1 (c=0.245, methanol) Analysis C₂₆H₃₃NO₆S₂:

Calc. %: C 60.09 H 6.40 N 2.69 Found: C 59.70 H 6.33 N 2.72¹H NMR (d₆-DMSO) δ: 1.09 (d, 3H), 1.15 (d, 6H), 2.08 (m, 1H), 2.75 (dd,1H), 2.98 (m, 2H), 3.16 (bs, 1H), 3.27 (m, 4H), 3.78 (bs, 1H), 4.34 (bd,1H), 4.43 (bd, 1H), 6.04 (s, 2H), 6.84 (t, 1H), 7.06 (m, 3H), 7.18 (d,1H), 7.24 (t, 1H), 7.39 (d, 1H), 8.52 (bs, exchangeable), 8.76 (bs,exchangeable).

Reference Example 263-(R)-[3-(2-Hydroxy-6-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(1-26)

The compound (1-26) is obtained, in the form of a colorless oil, bycarrying out the preparation as in reference example 17 but by replacing3-(R)-[3-(2-methoxymethoxy-3-methylphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIb) with3-(R)-[3-(2-methoxymethoxy-6-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine(VIj).

Yield: 88% ¹H NMR (d₆-DMSO) δ: 0.95 (d, 3H), 1.61 (m, 1H), 2.40 (s, 3H),2.60 (m, 2H), 2.77 (dd, 1H), 2.88 (dd, 1H), 3.00 (m, 2H), 3.88 (dd, 1H),4.11 (dd, 1H), 6.71 (m, 2H), 6.99 (m, 3H), 7.17 (m, 1H), 7.33 (dd, 1H).

0.39 g (0.001 mol) of the product (1-26) is dissolved in 3 ml ofmethanol and then 0.105 g (0.0009 mol) of maleic acid, dissolved in 2 mlof methanol, is added. The solution obtained is concentrated and thenethyl ether is added. The precipitate formed is filtered out, washedwith ethyl ether and dried under vacuum at 50° C. 0.37 g (0.0007 mol) ofthe maleate of the compound (1-26) is obtained in the form of a whitesolid.

M.p.: 153–4° C. [α]=0 (c=0.2, methanol) Analysis C₂₄H₂₉NO₆S₂:

Calc. %: C 58.63 H 5.95 N 2.85 Found: C 58.53 H 5.97 N 3.04¹H NMR (d₆-DMSO) δ: 1.06 (d, 3H), 1.96 (m, 1H), 2.42 (s, 3H), 2.71 (dd,1H), 2.91 (dd, 2H), 3.15 (m, 1H), 3.24 (bs, 2H), 3.76 (bs, 1H), 4.36 (m,2H), 6.04 (s, 2H), 6.74 (d, 2H), 7.05 (m, 3H), 7.24 (m, 1H), 7.39 (dd,1H).

The compounds of formula (1) and their therapeutically acceptable saltsexhibit advantageous pharmacological properties, in particular cardiaccytoprotective properties.

This is because they are active with regard to the cardiomyocyte byinhibiting the contraction of the rat isolated left atrium induced byveratrine and because it is accepted that veratrine slows down theinactivation of the sodium channel and produces a long-lasting sodiumcurrent which reproduces the sodium overload observed during ischemia.This pharmacological test is carried out according to the techniquedescribed in Naunyn-Schmiedeberg's Arch. Pharmacol., 1993, 348, 184according to the following protocol.

Male Wistar rats (OFA, Iffa Credo, France) weighing 400–450 g are used.The animals are placed in quarantine for 4 to 8 days with free access tostandardized laboratory food before they are used in the experiments.The animals are housed individually 24 hours before the tests. Waterfiltered through a 0.22 μm filter is freely available from an automaticdispenser. The quarantine area and the experimental laboratory areair-conditioned (temperature: 20±3° C.; relative humidity: 55±5%) andare illuminated from 7 a.m. to 7 p.m. All the rats are treated accordingto the code of ethics for laboratory animals (Guide for the Care and Useof Laboratory Animals, U.S. Department of Agriculture, Public HealthService, National Institutes of Health publication No. 85–23, Revised1985) and the protocol (No. 31) is carried out in accordance with therecommendations of the local research animals ethics committee.

The animals are sacrificed using a lethal dose of sodium pentobarbital(50 mg/kg) administered intra-peritoneally. The thorax is opened and theleft atrium is rapidly excised and mounted, in the vertical position, inan organ vessel comprising 20 ml of Krebs liquid (NaCl, 119 mmol; KCl,5.6 mmol; MgSO₄, 1.17 mmol; CaCl₂, 2.1 mmol; NaH₂PO₄, 1 mmol; NaHCO₃, 25mmol; glucose, 10 mmol; pH=7.4). The bath is maintained at a constanttemperature of 34° C. while continuously bubbling in an O₂/CO₂ (95:5)mixture. The atrium is stimulated by means of an electric current with afrequency of 4 Hz (duration of the pulse 1 ms) using two electrodes(Campden, Stimulator 915, Phymep, Paris, France). The contractile forceis measured using a sensor (Statham; UC2). The amplifier is connected toan MP 100 interface (Biopac Systems, Goleta, Calif., USA) and the analogsignal is digitized simultaneously and analyzed (Acknowledge III, BiopacSystems). After 30 min of returning to equilibrium, a concentration ofthe test product or of the vehicle is introduced into the organ vessel.Fifteen minutes after the introduction of the product or of the vehicle,veratrine (100 μg/ml) is added. The systolic tension developed ismeasured before the introduction of the product or of the vehicle andimmediately before the addition of veratrine, so as to detect anynegative or positive inotropic effect of the product or vehicle. Themaximum amplitude of the contraction induced by the veratrine ismeasured independently of time. The test product is dissolved in DMSO inan amount sufficient to obtain a mother solution with a concentrationequal to 10 mmol. This mother solution is subsequently diluted withKrebs liquid to the desired concentration of test product. The highestconcentration of DMSO in fine is 0.1%.

Statistical analysis of the intergroup results (product versus vehicle)is carried out by an analysis of variance ANOVA followed by a Dunetttest.

The cytoprotective activity of the compounds of the invention was alsodemonstrated in vivo in an occlusion-reperfusion model in theanesthetized animal.

Thus, the compounds of the invention are capable of normalizing theelectrical disturbances of the ECG brought about by a regional ischemiafollowed by a reperfusion, this being achieved without a significanteffect on the hemodynamic parameters. The test in question is carriedout according to the technique described in J. Cardiovasc. Pharmacol.,1995, 25, 126 according to the following protocol.

Male New Zealand rabbits (Elévage des Dombes, Romans,Chatillon-sur-Chalaronne, France) weighing 2.2 to 2.7 kg are used. Theanimals are placed in quarantine for 4 to 8 days with free access tostandardized laboratory food before they are used in the experiments.The animals are housed individually. Water filtered through a 0.22 μmfilter is freely available from an automatic dispenser. The quarantinearea and the experimental laboratory are air-conditioned (temperature:20±3° C.; relative humidity: 55±5%) and are illuminated from 7 a.m. to 7p.m. All the animals are treated according to the code of ethics forlaboratory animals (Guide for the Care and Use of Laboratory Animals,U.S. Department of Agriculture, Public Health Service, NationalInstitutes of Health publication No. 85-23, Revised 1985) and theprotocol (No. 28) is carried out in accordance with the recommendationsof the local research animals ethics committee. The animals areanesthetized using sodium pentobarbital (60 mg/kg) administeredintravenously (i.v.) via a catheter positioned in the vein of the ear.The animals are instrumented with respiratory assistance (683rodent/small animal ventilator, Havard Apparatus, Les Ulis, France). Thegas mixture inhaled is enriched in oxygen. The respiratory rhythm, theflow volume and the percentage of oxygen in the gas mixture are adjustedso as to keep the gases in the blood within physiological limits. Apolyethylene catheter, introduced into the carotid artery, is used bothfor the measurements of arterial pressure and to take the samplesintended for the analysis of the blood gases (ABL 510, Radiometer,Copenhagen, Denmark). Anesthesia is maintained by injections of sodiumpentobarbital as required. The body temperature of the animals is keptat 38–39° C. throughout the duration of the experiment using a heatingblanket (Homothermic Blanket, Havard Apparatus). The various cathetersare rinsed using a sterile saline solution (0.9%) comprising heparin(150 U.I./ml). The ECG (DII derivation) is recorded in order to measurethe variations in the heart rate (RR interval) and in the amplitude ofthe ST segment. The arterial pressure is digitized and analyzedsimultaneously (Dataflow®, Crystal Biotech, Northboro, Mass.). Thethorax of the animal is opened at the fourth intercostal space and thepericardium is incised so as to reveal the left coronary artery. Aligature (Vicryl®, 5/0, Ethicon, Paris, France) is passed under thisartery. After examining the ECG in order to detect any signs ofmyocardial lesions (persistent rise of the ST segment above 0.25 mV), aperiod of stabilization lasting 30 min is systematically observed. Anyanimal showing a possible myocardial lesion is excluded from the study.The test compound or the vehicle is administered per os (p.o.), as a 1%solution in methyl-cellulose, in a proportion of 1 ml/kg via a gastrictube made of flexible rubber. Anesthesia is produced 60 min afteradministration of the test compound or of the vehicle. The main coronaryartery is then ligated for 10 min, i.e. 60 min after anesthesia, thetension in the ligature is subsequently relaxed completely for 10 minand then reestablished at the end of the procedure. The heart is excisedand perfused using a formaldehyde solution (10%). The surface not fixedby the formaldehyde is regarded as the surface at risk.

The parameters measured in the experiment are:

-   -   the systolic and diastolic arterial pressure;    -   the heart rate (measured from the RR intervals);    -   the amplitude of the ST segment.

All the parameters mentioned above are measured preocclusion, 5 min and10 min postocclusion and then 5 min, 10 min and 20 min afterreperfusion.

The results obtained for some compounds of formula (1), given asnonlimiting examples, and those obtained for the derivative R 56865(blocker of noninactivated sodium channels), atenolol (β-blocker) anddiltiazem (blocker of calcium channels), chosen as reference product,are reported in the table below:

ST segment % Compound Contraction inhibition at Arterial Heart rate orwith veratrine 2.5 mg/kg pressure % control Inhibition IC₅₀ p.o. %variation variation 1-1 0.64 85 8 2 1-7 0.14 69 5 0 R 56865 0.25 0 — —Atenolol >10 49 −9 −13 Diltiazem >10 30 −27 −5

The results of the tests therefore show that the compounds of formula(1);

-   -   oppose the long-lasting sodium current induced by veratrine;    -   tend to normalize the electrical disturbances in the ECG brought        about by a regional ischemia followed by a reperfusion.

The in vitro activity of these compounds of the invention is of the sameorder of magnitude as that of the product R 56865, atenolol anddiltiazem being inactive in this test.

The in vivo activity of these compounds of the invention is much greaterthan that of all the control products (R 56865, atenolol and diltiazem).Furthermore, it should be pointed out that, at the dose of 2.5 mg/kgadministered by the oral route, these products of the inventioneffectively inhibit the raising of the ST segment without significantlymodifying the heart rate and the arterial pressure, contrary to thecontrol products active in this model (atenolol and diltiazem).

The molecules of the invention thus oppose the sodium overload byspecifically interacting at the noninactivated sodium channel. They showan in vivo cardioprotective activity in the absence of hemodynamiceffect.

For this reason, the compounds of the invention and theirtherapeutically acceptable salts are potentially of use as medicaments,in particular in the field of cardiology, especially in the treatment ofcertain cardiovascular pathologies, such as, for example, cardiacischemia, stable angina, unstable angina, cardiac insufficiency,myocardial infarction, cardiac rhythm disorders or long QT syndrome ofcongenital origin.

The compounds of the invention, which can also possess a sufficientactivity in modulating neuronal sodium channels and which haveappropriate pharmacokinetic properties, may be active with regard to thecentral and/or peripheral nervous system. Consequently, some compoundsof the invention are regarded as also being able to be of use in thetreatment of diseases or disorders such as, for example, cerebralischemia, transitory ischemic attack, neuropathies of a traumatic orischemic nature, neurodegenerative diseases (Trends in PharmacologicalScience, 1995, 16, 309; Clin. Exp. Pharmacol. Physiol., 2000, 27(8),569), epilepsy and pain of neuropathic origin (Brain Res., 2000, 871(1),98).

The compounds of the invention can be administered orally, nasally,sublingually, rectally or parenterally. Two preparations of thecompounds of the invention are given hereinafter as nonlimitingformulation examples. The ingredients, and others, which aretherapeutically acceptable can be introduced in other proportionswithout altering the scope of the invention. The terms “activeingredient” used in the formulation examples hereinbelow refer to acompound of formula (1) or an addition salt or optionally a hydrate ofan addition salt of the compound of formula (1) with a pharmaceuticallyacceptable inorganic acid or organic acid.

Formulation Example 1 Tablets

Active ingredient 100 g Lactose 570 g Corn starch 200 g Sodium laurylsulfate  5 g Polyvinylpyrrolidone  10 g Microcrystalline cellulose 100 gSaturated vegetable oil  15 gi.e. 10,000 tablets, each comprising 10 mg of the active ingredient.

Formulation Example 2 Injectable Solution

Active ingredient 10 mg Acetic acid 20 mg Sodium acetate 5.9 mg Steriledistilled water q.s. for 2 ml Sterile bottle or vial.

1. A 3-arylthiopropylamino-3,4-dihydro-2H-1,5-aryloxathiepine derivativeof general formula (1)

wherein: R₁ and R₂, which are identical or different, represent: ahydrogen atom; a fluorine atom or a chlorine atom; a hydroxyl group; alinear or branched (C₁–C₃) alkyl; a cyclopropyl radical; a cyclopropoxyradical; R₃ represents: a linear or branched (C₁–C₃) alkyl radical; ahydroxyl group or a methoxy radical; R₄ represents: a hydrogen atom or amethyl radical; and R₅ and R₆, which are identical or different,represent: a hydrogen atom; a linear or branched (C₁–C₃) alkyl radical;a linear or branched (C₁–C₃) alkoxy radical; a linear or branched(C₁–C₃) alkylthio radical; an alkylamino radical; provided that, when R₄represents a methyl radical, then R₅ represents a hydrogen atom, a(C₁–C₃) alkoxy radical, a linear or branched (C₁–C₃) alkylthio radicalor an alkylamino radical, its addition salts and the hydrates of theseaddition salts with pharmaceutically acceptable inorganic acids orpharmaceutically acceptable organic acids, and its tautomeric forms, theenantiomers and the mixtures of enantiomers, and the stereoisomers, pureor as a racemic or nonracemic mixture.
 2. The derivative of claim 1,wherein; R₁ and R₂, which are identical or different, represent: ahydrogen atom; a fluorine atom or a chlorine atom; a hydroxyl group; analkyl radical selected from methyl, ethyl, propyl and isopropylradicals; a cyclopropyl radical; an alkoxy radical selected frommethoxy, ethoxy, propoxy and isopropoxy radicals; a cyclopropoxyradical; R₃ represents; an alkyl radical selected from methyl, ethyl,propyl and isopropyl radicals; a hydroxyl group or a methoxy radical; R₄represents: a hydrogen atom or a methyl radical; and R₅ and R₆, whichare identical or different, represent: a hydrogen atom; an alkyl radicalselected from methyl, ethyl and isopropyl radicals; an alkoxy radicalselected from methoxy, ethoxy, propoxy and isopropoxy radicals; analkylthio radical selected from methylthio, ethylthio and isopropylthioradicals; an alkylamino radical selected from N-methylamino andN,N-dimethylamino radicals; its addition salts and the hydrates of theseaddition salts with pharmaceutically acceptable inorganic acids orpharmaceutically acceptable organic acids, and its tautomeric forms, theenantiomers and the mixtures of enantiomers, and the stereoisomers, pureor as a racemic or nonracemic mixture.
 3. The derivative of claim 1,selected from3-[3-(2-methoxyphenylthio)-2-methoxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-methoxyphenylthio)-2-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxyphenylthio)-2-hydroxypropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-methoxyphenylthio)-2-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-methoxyphenylthio)-2-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-methoxyphenylthio)-2-(n-propyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-methoxyphenylthio)-2-(isopropyl)propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-methoxyphenylthio)-2-methylpropyl]amino-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-methoxyphenylthio)-2-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-3-methylphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxyphenylthio)-2-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-3-ethylphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2,3-dihydrobenzofuran-7-thio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-3-methylphenylthio)-2-ethylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-3-methylphenylthio)-2-(isopropyl)-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-3-methylphenylthio)-2-methylpropyl]-amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-3-methoxyphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2,3-dimethoxyphenylthio)-2-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-3-(isopropyl)phenylthio)-2-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-[3-(2-hydroxy-6-methylphenylthio)-2-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine,its addition salts and the hydrates of these addition salts withpharmaceutically acceptable inorganic acids or pharmaceuticallyacceptable organic acids, and its tautomeric forms, the enantiomers andthe mixtures of enantiomers, and the stereoisomers, pure or as a racemicor nonracemic mixture.
 4. A process for the preparation of the compoundof general formula (1) of claim 1 in which R₃ represents a linear orbranched (C₁–C₃) alkyl radical or a methoxy radical and R₄ represents amethyl radical, wherein an amine of formula (I)

in which R₁ and R₂ are as defined in claim 1, or one of its salts, isreacted with an aldehyde of formula (II)

in which R₃ represents a linear or branched (C₁–C₃) alkyl radical or amethoxy radical, R₄ represents a methyl radical and R₅ and R₆ are asdefined in claim 1, in the presence of a reducing agent and at atemperature of between −20° C. and +25° C., to give a compound offormula (1)


5. A process for the preparation of the compound of general formula (1)of claim 1 in which R₃ represents a linear or branched (C₁–C₃) alkylradical or a methoxy radical and R₄ represents a hydrogen atom, whereinan amine of formula (I)

in which R₁ and R₂ are as defined in claim 1, or one of its salts, isreacted with a compound of formula (V)

in which R₃ represents a linear or branched (C₁–C₃) alkyl radical or amethoxy radical and R₅ and R₆ are as defined in claim 1, in the presenceof a reducing agent and at a temperature of between −20° C. and +25° C.,to give a compound of formula (VI)

which is hydrolyzed to give a compound of formula (1)

in which R₃ represents a linear or branched (C₁–C₃) alkyl radical or amethoxy radical and R₄ a hydrogen atom.
 6. A process for the preparationof the compound of general formula (1) of claim 1 in which R₃ is ahydroxyl group, wherein an epoxide of formula (III)

in which R₁ and R₂ are as defined in claim 1, is reacted with anarylthiol of formula (IV)

in which R₄, R₅ and R₆ are as defined in claim 1, in a protic solvent,in the presence of an inorganic base and at a temperature of between 20°C. and 70° C., to give a compound of formula (1)

in which R₁, R₂, R₄, R₅ and R₆ are as defined in claim 1 and R₃ is ahydroxyl group.
 7. The derivative of general formula (1) of claim 1,which has the (R) absolute configuration at the C(3) asymmetric carbonatom of the 3,4-dihydro-2H-1,5-benzoxathiepine fragment and the (S)absolute configuration at the asymmetric carbon atom which carries theR₃ group.
 8. The derivative of claim 7, which is selected from thefollowing stereoisomers:3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methoxypropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-methoxyphenylthio)-2-(S)-hydroxypropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxyphenylthio)-2-(S)-hydroxypropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-methoxyphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-methoxyphenylthio)-2-(S)-(n-propyl)propyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-methoxyphenylthio)-2-(S)-(isopropyl)-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]-amino-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]-amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine,3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxyphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxy-3-ethylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2,3-dihydrobenzofuran-7-thio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-ethylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-(isopropyl)-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxy-3-methylphenylthio)-2-(S)-methylpropyl]amino-6-methyl-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxy-3-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2,3-dimethoxyphenylthio)-2-(S)-methylpropyl]-amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxy-3-isopropylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine;3-(R)-[3-(2-hydroxy-6-methylphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine,their addition salts and the hydrates of these addition salts withpharmaceutically acceptable inorganic acids or pharmaceuticallyacceptable organic acids, and their tautomeric forms, the enantiomersand the mixtures of enantiomers, and the stereoisomers, pure or as aracemic or nonracemic mixture.
 9. A compound as claimed in claim 1 asmedicament.
 10. A pharmaceutical composition, comprising, as activeingredient, at least one compound of claim 1 in combination with aninert pharmaceutical carrier or other pharmaceutically acceptablevehicles.
 11. A method of treating a living animal body afflicted withstable angina, unstable angina, cardiac insufficiency, long QT syndromeof congenital origin, myocardial infarction and cardiac rhythmdisorders, comprising the step of administering an amount of a compoundof claim 1, which is effective for alleviation of such condition.
 12. Amethod of treating a living animal body afflicted with cerebralischemia, transitory ischemic attack, neuropathies of a traumatic orischemic nature, and epilepsy, comprising the step of administering anamount of a compound of claim 1, which is effective for alleviation ofsuch condition.
 13. A method of treating a living animal body afflictedwith pain of neuropathic origin and of neurodegenerative diseases,comprising the step of administering an amount of a compound of claim 1,which is effective for alleviation of such condition.